Azaindolylpiperidine derivatives as antihistaminic and antiallergic agents

ABSTRACT

This invention is directed to selective antagonists of H 1  histamine receptors having the general formula (I); to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy.

The present invention relates to novel azaindolylpiperidine compoundsand pharmaceutically acceptable salts thereof. These compounds areantagonists of H₁ histamine receptors and are thus useful for thetreatment of bronchial asthma, allergic rhinitis, conjunctivitis,dermatitis, urticaria and other allergic diseases.

Due to their capability to cross the blood-brain barrier, mostcommercial antihistamines produce adverse side-effects such assleepiness and sedation. Antihistamines having an indolylpiperidine corehave been disclosed in EP 224919 and WO 0075130. It has now been foundthat replacing one or more carbon atoms of the six-membered ring of theindolyl moiety by the corresponding number of nitrogen atomsdramatically decreases the capability of the compounds to cross theblood-brain barrier, diminishing the occurrence of side effects.

Thus, the present invention provides certain novel azaindolylpiperidinecompounds having improved antihistaminic and antiallergic activities anda reduced occurrence of sedative and cardiovascular side effects.Azaindolylpiperidines of a different general structure have beendisclosed in EP 842934 as serotonin agonists.

Further objectives of the present invention are to provide a method forpreparing said compounds; pharmaceutical compositions comprising aneffective amount of said compounds; the use of the compounds in themanufacture of a medicament for the treatment of diseases susceptible ofbeing improved by antagonism of H₁ histamine receptors, such as allergicdiseases; and methods of treatment of diseases susceptible toamelioration by antagonism of H₁ histamine receptors, such as allergicdiseases, comprising the administration of the compounds of theinvention to a subject in need of treatment.

In accordance with the present invention, novel azaindolylpiperidinecompounds represented by the general formula I are provided

wherein:

-   each of A, B, D and E independently represents a nitrogen atom or a    —CR₁— group, with the proviso that at least one of A, B, D or E is a    nitrogen atom;-   R₁ represents a hydrogen or a halogen atom, or a hydroxy, alkyl,    alkenyl, alkynyl, alkoxy, alkylthio, amino, monalkyalmino,    dialkylamino, nitro, cyano or acylamino group, the hydrocarbon    chains of these groups being optionally substituted by one or more,    for example, 1, 2, 3 or 4, further substituents selected from    halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl,    alkoxycarbonyl, amino, monoalkylamino, dialkylamino and    hydroxycarbonyl groups;-   R₂ represents a hydrogen atom or a group of formula L₃-(W₂)_(p);-   L₁, L₂ and L₃ each independently represents a single bond or an    acyclic, straight or branched, saturated or unsaturated hydrocarbon    chain having from 1 to 10 carbon atoms, optionally containing 1 to 3    groups independently selected from —S—, —O— or —NR₃—, which replace    a corresponding number of non-adjacent carbon atoms, and wherein R₃    is selected from hydrogen or an alkyl group; the hydrocarbon chain    being optionally substituted by one or more, for example, 1, 2, 3 or    4, substituents selected from halogen, hydroxy, oxo, acylamino,    phenyl, alkoxycarbonyl and hydroxycarbonyl groups;-   R₄ and R₅ each independently represents a hydrogen or halogen atom,    a hydroxy group, or a group selected from one of alkyl, alkoxy,    alkenyl, alkynyl or phenyl, which is optionally substituted by one    or more, for example, 1, 2, 3 or 4, substituents selected from,    halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl,    alkoxycarbonyl, amino, monoalkylamino, dialkylamino and    hydroxycarbonyl groups;-   X represents —O— or —NR₆—;-   R₆ and R₇ each independently represents a hydrogen atom, a group of    formula —(CH₂)_(m)—W₃ or a group selected from alkyl, alkenyl or    alkynyl, which is optionally substituted by one or more, for example    1, 2, 3 or 4, substituents selected from —(CH₂)_(m)—W₃,    —O—(CH₂)_(m)—W₃, —S—(CH₂)_(m)—W₃, —NR₃—(CH₂)_(m)—W₃, hydroxy, oxo,    halogen, alkoxy, alkylthio, amino, monoalkylamino, and dialkylamino;    the alkyl chains in the alkoxy, alkylthio, monoalkylamino and    dialkylamino substituents being optionally substituted by one or    more, for example 1, 2, 3 or 4, further substituents selected from    —(CH₂)_(m)—W₃, hydroxy, oxo, halogen, alkoxy, alkylthio, amino,    monoalkylamino and dialkylamino groups;-   W₁, W₂ and W₃ each independently represents a 3- to 7-membered    aromatic or non-aromatic cyclic group containing from 0 to 4    heteroatoms selected from N, O and S, which is optionally fused to    another 3- to 7-membered aromatic or non-aromatic cyclic group    containing from 0 to 4 heteroatoms selected from N, O and S; the    cyclic groups being optionally substituted by one or more, for    example 1, 2, 3 or 4, substituents selected from halogen, alkyl,    alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl,    hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino,    dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkylcarbonyl,    alkoxycarbonyl, acylamino, carbamoyl, and alkylcarbamoyl groups; the    hydrocarbon chains and the cyclic moieties of these substituents    being optionally substituted by one or more, for example 1, 2, 3 or    4, further substituents selected from halogen, hydroxy, oxo, alkoxy,    alkylthio, acylamino, carbamoyl, alkylcarbamoyl, hydroxyalkoxy,    phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and    hydroxycarbonyl groups;-   m is an integer from 0 to 4;-   n and p are independently 0 or 1;-   q is an integer from 1 to 9;-   and N-oxides and pharmaceutically acceptable salts thereof;-   with the proviso that the compound of formula I is not the    tert-butyl ester of    4-(5-amino-1H-pyrrolo[3,2-b]pyridin-3-yl)piperidine-1-carboxylic    acid.

As used herein, a hydrocarbon chain is a straight or branched non-cyclicsequence of carbon atoms covalently linked by single, double or triplebonds, and substituted by hydrogen atoms, for example straight orbranched alkyl, alkenyl or alkynyl groups, moieties or chains.Typically, the hydrocarbon chains, contain from 1 to 10 carbon atoms.

As used herein, an alkyl, alkenyl or alkynyl group or moiety is astraight or branched group or moiety. Typically it is a C₁-C₁₀ group ormoiety, for example a C₁-C₆ group or moiety, preferably a C₁-C₄ group ormoiety. Examples include methyl, ethyl, i-propyl, n-propyl, n-butyl,t-butyl, allyl, 2-propenyl and 3-butynyl. Where a group contains two ormore alkyl, alkenyl or alkynyl moieties, these moieties may be the sameor different. When an alkyl, alkenyl or alkynyl chain, group or moietycarries 2 or more substituents, the substituents may be the same ordifferent.

As used herein, an alkylene group or moiety is a divalent alkyl moietytypically having from 1 to 6, for example from 1 to 4, carbon atoms.Examples of C₁-C₄ alkylene groups include methylene, ethylene, propyleneand butylene groups. When an alkylene or alkylenedioxy group is presentas a substituent on another group it shall be deemed to be a singlesubstituent, rather than a group formed by two substituents.

As used herein, the alkyl chains present in the alkoxy, alkylthio,monoalkylamino, dialkylamino, hydroxyalkoxy, alkylcarbonyl,alkoxycarbonyl, alkylcarbamoyl and alkylenedioxy groups are typicallystraight or branched alkyl chains containing from 1 to 6 carbon atoms.

As used herein, an acyl group or moiety typically has from 2 to 7 carbonatoms. Thus, it is typically a group of formula —COR wherein R is ahydrocarbon chain group having from 1 to 6 carbon atoms. Preferably, itis a group of formula —COR wherein R is a C₁-C₆ alkyl group.

As used herein, an aryl group or moiety is typically a C₆-C₁₀ aryl groupor moiety such as phenyl or naphthyl. Phenyl is preferred. When an arylgroup or moiety carries 2 or more substituents, the substituents may bethe same or different.

As used herein, a heteroaryl group or moiety is typically a 5- to10-membered aromatic ring, such as a 5- or 6-membered ring, containingat least one heteroatom selected from O, S and N. Examples includepyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, oxadiazolyl,oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrazolidinyl,pyrrolyl and pyrazolyl groups. Oxadiazolyl, oxazolyl, pyridyl, pyrrolyl,imidazolyl, thiazolyl, thiadiazolyl, thienyl, furanyl, pyrazinyl andpyrimidinyl groups are preferred. When a heteroaryl group or moietycarries 2 or more substituents, the substituents may be the same ordifferent.

As used herein, a cycloalkyl group typically has from 3 to 6 carbonatoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. It is preferably cyclopropyl, cyclopentyl or cyclohexyl.When a cycloalkyl group carries 2 or more substituents, the substituentsmay be the same or different.

As used herein, a heterocyclyl group is typically a non-aromatic,saturated or unsaturated C₃-C₁₀ carbocyclic ring in which one or more,for example 1, 2, 3 or 4 of the carbon atoms are replaced by aheteroatom selected from N, O and S. Saturated heterocyclyl groups arepreferred. Examples of suitable heterocyclyl groups include piperidinyl,piperazinyl, morpholinyl, 4,5-dihydro-oxazolyl, 3-aza-tetrahydrofuranyl,imidazolidinyl and pyrrolidinyl groups. Where a heterocyclyl groupcarries 2 or more substituents, the substituents may be the same ordifferent.

As used herein, some of the atoms, groups, moieties, chains or cyclespresent in the general structures of the invention are “optionallysubstituted”. This means that these atoms, groups, moieties, chains orcycles can be either unsubstituted or substituted by one or more, forexample 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound tothe unsubstituted atoms, groups, moieties, chains or cycles are replacedby chemically acceptable atoms, groups, moieties, chains or cycles.

As used herein, when one of the substituents is a halogen atom, it ispreferably a chlorine, fluorine or bromine atom.

Compounds of the formula (I) containing one or more chiral centre may beused in enantiomerically or diastereoisomerically pure form, or in theform of a mixture of isomers.

As used herein, an N-oxide is formed from the pyridines present in themolecule, using a convenient oxidising agent.

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids, for example hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic and nitric acid and organic acids,for example citric, fumaric, maleic, malic, ascorbic, succinic,tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic,benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptablebases include alkali metal (e.g. sodium or potassium) and alkali earthmetal (e.g. calcium or magnesium) hydroxides and organic bases, forexample alkyl amines, aralkyl amines and heterocyclic amines.

Preferred compounds of the invention are those wherein only one or twoof A, B, D or E is a nitrogen atom. When only one is nitrogen it ispreferably at positions D or E. When two of them are nitrogen they arepreferably at positions A and D or B and E.

Also preferred are compounds wherein each R₁ is independently selectedfrom a hydrogen or halogen atom or an alkyl, or alkoxy group. Morepreferably, R₁ is hydrogen, chlorine; fluorine or methoxy and still morepreferably R₁ is hydrogen.

Further preferred compounds are those wherein each of L₁, L₂ and L₃independently represents a single bond or an alkyl, oxyalkyl,aminoalkyl, thioalkyl or alkoxyalkyl group. When L₁ or L₂ represents anoxyalkyl, aminoalkyl or thioalkyl group the orientation of the group istypically such that the alkyl moiety is attached to the N atom. Mostpreferred are compounds wherein L₁ is an alkyl, oxyalkyl; aminoalkyl orthioalkyl group, for example methyl, ethyl, n-propyl, oxyethyl,oxypropyl, aminoethyl or thioethyl; L₂ is a single bond or an alkylgroup, for example methyl or ethyl; and L₃ is a single bond or an alkyl,oxyalkyl or alkoxyalkyl group, for example methyl, ethyl, n-propyl,isopropyl, butyl, oxyethyl, methoxyethyl or ethoxyethyl.

W₁ is preferably an aromatic monocyclic group which is optionallysubstituted by one or more, for example, 1, 2, 3 or 4, substituentsselected from halogen atoms, alkyl or alkoxy groups. More preferably W₁is selected from a phenyl, furanyl or thienyl group, which is optionallysubstituted by one or more, for example 1, 2, 3 or 4, substituentsselected from halogen, alkyl or alkoxy, such as fluorine, chlorine,bromine, methyl or methoxy. Most preferred are compounds wherein W₁ is aphenyl group optionally substituted by one or more, for example 1, 2, 3or 4, substituents selected from halogen, alkyl or alkoxy, such asfluorine, chlorine, bromine, methyl or methoxy.

Alternatively, in yet other preferred compounds of the invention n is 0.

W₂ is preferably a cycloalkyl group, for example cyclopropyl, cyclobutylor cyclopentyl, a phenyl group, or a 5- or 6-membered heterocyclylgroup, for example a tetrahydropyranyl, furanyl, thienyl, pyrrolyl,pyridinyl, oxetanyl or dioxanyl group. More preferably W₂ is selectedfrom cyclopropyl, phenyl, pyridinyl, furanyl and thienyl.

W₂ is optionally substituted by one or more, for example 1, 2, 3 or 4,substituents selected from halogen, alkyl or alkoxy, such as fluorine,chlorine, bromine, methyl, ethyl or methoxy.

Alternatively, in yet other preferred compounds of the invention p is 0or R₂ is hydrogen.

In the preferred compounds of the invention R₄ and R₅ each independentlyrepresents a hydrogen or halogen atom, a C₁-C₄ alkyl group or a phenylgroup, which is optionally substituted by one or more, for example 1, 2,3 or 4, substituents selected from halogen, alkyl or alkoxy, such asfluorine, chlorine, bromine, methyl, ethyl or methoxy. Most preferablyR₄ and R₅ are both hydrogen.

In the most preferred compounds of the invention X is —O— and R₇ ishydrogen, alkyl or a —(CH₂)_(n)-phenyl group, wherein n is 0 or 1, forexample methyl, ethyl, tert-butyl, phenyl or benzyl, excluding thetert-butyl ester of4-(5-amino-1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidine-1 rboxylic acid.

Alternatively, when X is —N—R₆, the most preferred compounds are thosewherein Re and R₇ are independently hydrogen, alkyl or a—(CH₂)_(n)-phenyl group, wherein n is 0 or 1, for example methyl, ethyl,tert-butyl, phenyl or benzyl.

Particular individual compounds of the invention include:

-   1.    3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoic    acid-   2.    3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoic    acid-   3.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-yl]ethoxy}benzoic    acid-   4.    3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoic    acid-   5.    5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl}-2-methoxybenzoic    acid-   6.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylethoxy)benzoic    acid-   7.    5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   8.    2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   9.    3-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   10.    5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2methoxy-benzoic    acid-   11.    2-{2-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-ylypiperidin-1-yl]-ethoxy}benzoic    acid-   12.    3-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   13.    2-methoxy-5-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   14.    2-{2-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   15.    3-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   16.    2-methoxy-5-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   17.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   18.    3-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic    acid-   19.    5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}2-methoxybenzoic    acid-   20.    2-(2-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   21.    2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic    acid-   22.    2,4-dimethoxy-3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic    acid-   23.    2-methoxy-6-(2-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoic    acid-   24.    5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxybenzoic    acid 25.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   26.    3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   27.    2-{2-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   28.    3-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   29.    5-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   30.    2-{2-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   31.    3-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   32.    5-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   33.    2-(2-{4-[1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}ethoxy)-benzoic    acid-   34.    4-{4-[1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-butyric    acid-   35.    (2-{4-{1-(4-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-acetic    acid-   36.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic    acid-   37.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic    acid-   38.    4-chloro-2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoic    acid-   39.    5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-fluorobenzoic    acid-   40.    3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic    acid-   41.    3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2,4-dimethoxybenzoic    acid-   42.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-6-methoxybenzoic    acid-   43.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-methoxybenzoic    acid-   44.    4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   45.    2-fluoro-5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   46.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxybenzoic    acid-   47.    3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   48.    3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2,4-dimethoxybenzoic    acid-   49.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy)-6-methoxybenzoic    acid-   50.    2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxybenzoic    acid-   51.    2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxybenzoic    acid-   52.    4-chloro-2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   53.    2-fluoro-5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   54.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic    acid-   55.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic    acid-   56.    4-chloro-2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoic    acid-   57.    5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-fluorobenzoic    acid-   58.    3-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic    acid-   59.    3-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2,4-dimethoxybenzoic    acid-   60.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-6-methoxybenzoic    acid-   61.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-methoxybenzoic    acid-   62.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-3-methoxybenzoic    acid-   63.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-chlorobenzoic    acid-   64.    5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-fluorobenzoic    acid-   65.    3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   66.    3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2,4-dimethoxybenzoic    acid-   67.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-6-methoxybenzoic    acid-   68.    2-{2-[4-(1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   69.    4-[4-(1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-butyric    acid-   70.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   71.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic    acid-   72.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic    acid-   73.    4-chloro-2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   74.    5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}2-methoxybenzoic    acid-   75.    4-bromo-3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic    acid-   76.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxybenzoic    acid-   77.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   78.    5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   79.    3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   80.    4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   81.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy)-benzoic    acid-   82.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy)-3-methoxy-benzoic    acid-   83.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-methoxy-benzoic    acid-   84.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-chlorobenzoic    acid-   85.    5-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   86.    4-bromo-3-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   87.    3-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   88.    5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic    acid-   89.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}ethoxy)-benzoic    acid-   90.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic    acid-   91.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}ethoxy)-4-methoxybenzoic    acid-   92.    4-chloro-2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   93.    (2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl)-ethoxy)acetic    acid-   94.    2-{2-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   95.    2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic    acid-   96.    5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid-   97.    4-methoxy-2-{2-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid-   98.    2-methoxy-5-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-ylmethyl]-benzoic    acid-   99.    2-(2-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   100.    2-(2-{4-[1-(2-ethoxyethyl)-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic    acid-   101.    3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoic    acid ethyl ester-   102.    3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoic    acid methyl ester-   103.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-yl]ethoxy}benzoic    acid methyl ester-   104.    3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidin-1-ylmethyl}benzoic    acid methyl ester-   105.    5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-1-ylmethyl}-2-methoxybenzoic    acid ethyl ester-   106.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylethoxy)benzoic    acid methyl ester-   107.    5-[4-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic    acid ethyl ester-   108.    2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}ethoxy)-benzoic    acid methyl ester-   109.    5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxybenzoic    acid ethyl ester-   110.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylethoxy}-4-methoxybenzoic    acid methyl ester-   111.    2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl-piperidin-1-yl}-ethoxy)-benzoic    acid methyl ester-   112.    2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoic    acid methyl ester-   113.    2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoic    acid methyl ester-   114.    5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic    acid ethyl ester-   115.    4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1    carboxylic acid tert-butyl ester-   116.    4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic    acid ethyl ester-   117.    4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic    acid tert-butyl ester-   118. 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1 arboxylic    acid ethyl ester-   119.    4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic    acid ethyl ester-   120.    4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic    acid ethyl ester-   121.    4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic    acid ethyl ester-   122.    4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic    acid ethyl ester-   123.    4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic    acid tert-butyl ester-   124.    4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1    carboxylic acid ethyl ester-   125.    4-[1-(chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic    acid tert-butyl ester-   126. 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1    arboxylic add ethyl ester-   127.    4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic    acid ethyl ester-   128. 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperdine-1    arboxylic acid ethyl ester-   129. 4-(1-butyl-1H-pyrrolo[2,3]pyridin-3-yl)piperidine-1 arboxylic    add ethyl ester-   130.    4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic    add ethyl ester-   131.    3-(methyl-{2-[4-(1H-pyridin-2-ylmethyl-1H-pyrrolo[3,2-c]pyridin-3-yl)piperidin-1-yl]-ethyl}-amino)-benzoic    acid-   132.    6-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-hexanoic    acid-   133.    3-[4-(1-butyl-1H-pyrrolo[3,2-c]pyridin-3-yl)piperidin-1-ylmethyl]-isonicotinic    acid-   134.    5-{4-[1-(2-[1,4]dioxan-2-yl-ethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-piperidin-1-ylmethyl}2-fluorobenzoic    acid-   135.    (E)-4-{4-[7-(4-fluoro-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-piperidin-1-yl}-but-2-enoic    acid-   136.    5-(4-{7-[2-(4-methoxy-phenyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-piperidin-1-ylmethyl)-furan-2-carboxylic    acid-   137.    4-bromo-3-[4-(7-oxy-1-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic    acid-   138.    {2-[4-(4-chloro-1-thiophen-2-ylethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-acetic    acid-   139.    2-(2-{4-[7-fluoro-1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-thiophene-3-carboxylic    acid-   140.    2-(4-{2-[4-(2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic    acid-   141.    5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-pentanoic    acid (4-trifluoromethyl-phenyl)amide-   142.    3-[4-(3-{4-hydroxy-4-[5-methylsulfanyl-2-phenyl-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-furan-2-yl]-propionic    acid benzyl ester-   143.    1-[2-(2-{4-[1-(2-cyclopropylmethoxy-ethyl)-6,7-dimethoxy-1H-pyrrolo[3,2-b]pyridin-3-yl]-piperidin-1-yl}-ethylsulfanyl)ethyl]-piperidine-2-carboxylic    acid-   144.    2-{5-acetyl-2-[(3-(2-methoxy-ethoxy)methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-piperidin-1-yl}propyl)-methyl-amino]-phenoxy}-N,N-dimethyl-acetamide-   145.    (3-{3-[4-(2-bromo-7-isopropoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-2,2-dimethyl-piperidin-1-yl]-propanoyl}-5-chloro-phenoxy)acetic    add tert-butyl ester-   146.    5-(2-{4-[4-dimethylamino-1-(2-ethylsulfanyl-ethyl)-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-N,N-dimethyl-nicotinamide-   147.    [7-{1-[(E)-4-(5-{1-[(1,1-diphenyl-methyl)carbamoyl]-1-methyl-ethyl}-furan-2-yl)but-2-enyl]-piperidin-4-yl}5-(2-hydroxy-1-phenyl-ethyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl]-acetic    acid ethyl ester

In accordance with another embodiment, the present invention provides amethod for preparing the novel azaindolylpiperidine compoundsrepresented by formula 1. The compounds of formula I can be preparedaccording to Scheme 1 starting from an intermediate of general formulaIX wherein A, B, D, E, R₂, R₄, R₅ and q are as defined above.

Compound IX is deprotected by boiling it in the presence of an excess ofsodium or potassium hydroxide in an alcoholic solvent such as ethanol,isopropanol or n-butanol at a temperature between 80° C. and 180° C.This leads to a compound of general formula X, wherein A, B, D, E, R₂,R₄, R₅ and q are as defined above. Compounds of formula X are novel,with the exception of those wherein A is a nitrogen atom; D and E areboth —CH—; R₂, R₄ and R₅ are all hydrogen; and B is a —CR₁— group, R₁being an acylamino group. The novel compounds of formula X constitute afurther embodiment of the invention.

Further alkylation of compound X with a reactive intermediate of generalformula XI wherein L₁, L₂, W₁, n, X and R₇ are as defined above and Y isa leaving group, such as a chlorine or a bromine atom or a methanesulphonate, p-toluene sulphonate or a benzene sulphonate group, gives acompound of general formula I. This reaction is preferably carried outin an organic solvent such as toluene, dicloromethane, dioxane or methylisobutylketone at a temperature between 25° C. and 140° C. in thepresence of a base such as an alkali metal carbonate or bicarbonate,triethylamine or diisopropilethylamine. Occasionally, the solvent usedis dimethylformamide.

Compounds of general formula I wherein X is an oxygen atom are treatedwith sodium or potassium hydroxide in a solvent such as methanol,ethanol or tetrahydrofuran at a temperature between 25° C. and 60° C.Further treatment with an inorganic acid such as hydrochloric acidprovides the corresponding azaindolylpiperidine derivatives of generalformula XIV wherein A, B. D, E, L₁, L₂, R₂R₄, R₅, q, W₁ and n are asdefined above (see Scheme 2)

The intermediate of general formula IX can be prepared following twodifferent pathways (see Scheme 1).

According to the first pathway a compound of general structure IIIwherein A, B, D, E, R₄, R₅ and q are as defined above, is treated withtwo equivalents of ethyl chloroformate in the presence of a base such astriethylamine or pyridine at a temperature between 0° C. and roomtemperature to give a compound of general formula IV wherein A, B, D, E,R₄, R₅ and q are as defined above.

Compound IV is hydrogenated using palladium or platinum oxide as acatalyst in a solvent such as ethanol or methanol in neutral or acidicconditions at a pressure between 2 and 3 bar, to provide a compound ofgeneral formula V wherein A, B, D, E, R₄, R₅ and q are as defined above.

Subsequent deprotection of the carbamate moieties of the compound ofgeneral formula V by boiling it in the presence of an excess of sodiumor potassium hydroxide in an alcoholic solvent such as ethanol,isopropanol or n-butanol at a temperature between 80° C. and 180° C.gives a compound of formula VI wherein A, B, D, E, R₄, R₅ and q are asdefined above.

The piperidine moiety of compound VI is reprotected using the sameconditions as described above for preparing compound IV, giving acompound of general formula VII wherein A, B, D, E, R₄, R₅ and q are asdefined above.

Alkylation of compound VII with a reactive intermediate of generalformula VIII wherein R₂ is as defined above and Y is a leaving group,such as a iodine, chlorine or bromine atom or a methane sulphonate,p-toluensulphonate or a benzenesulphonate group, gives a compound ofgeneral formula IX. This reaction is preferably carried out in an inertsolvent such as dimethylformamide, tetrahydrofuran or ethyl ether at atemperature between 0° C. and 80° C. in the presence of an inorganicbase such as sodium hydride or sodium amide. Occasionally, the base usedis potassium carbonate in the presence of copper and copper oxide.

According to an alternative pathway (see Scheme 1), a compound ofgeneral formula III wherein A, B, D, E, R₄, R₆ and q are as definedabove, is treated with 1 equivalent of ethyl chloroformate in thepresence of a base such as triethylamine or pyridine at a temperaturebetween 0° C. and room temperature to give a compound of general formulaXII wherein A, B, D, E, R₄, R₆ and q are as defined above.

Compound XII is alkylated with the reactive intermediate VIII, which isas defined above, to give a compound of general formula XIII wherein A,B, D, E, R₂, R₄, R₅ and q are as defined above. This reaction ispreferably carried out in an inert solvent such as dimethylformamide,tetrahydrofuran or ethyl ether at a temperature between 0° C. and 80° C.in a presence of an inorganic base such as sodium hydride or sodiumamide.

Compound XIII is hydrogenated using palladium or platinum oxide as acatalyst in a solvent such as methanol or ethanol in neutral or acidicconditions at a pressure between 2 and 3 bar, to lead to the compound ofgeneral formula IX.

The final products of formula I are purified by chromatography or byrecrystallisation. Occasionally, the products are purified bypreparative HPLC-MS, using a C-18 column.

The starting compounds of the general formula II are either commerciallyavailable or prepared following described procedures (Heterocycles,1992, 34, 2379; J. Heterocyclic Chem. 1992, 29, 359); theazaindolylpiperidine derivatives of general formula III can be preparedfrom 4-piperidone as described in J. Med. Chem. 1992, 35, 4813.

The present invention will be further illustrated by the followingExamples. These Examples are given by way of illustration only and arenot to be construed as limiting. TABLE 1 List of examples according toScheme I

Ex- am- ple R1 R2 Mol. weight 1

393.484 2

415.491 3

445.516 4

407.511 5

437.537 6

437.537The sign (*) in the structures shows the point of attachment. It doesnot symbolise a carbon atom.

EXAMPLE 1 Preparation of3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoicacid A. Preparation of3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine

0.5 g (4.23 mmol) of 7-azaindole and 1.95 g (12.7 mmol) of 4-piperidinemonohydrate hydrochloride were added to an ice-cooled solution of 0.9 g(16.07 mmol) of potassium hydroxide in 15 ml of methanol. The mixturewas warmed to room temperature and then refluxed for 18 hours. Oncecooled to room temperature, the formed solid was isolated by suctionfiltration. The filtered solution was concentrated and the residue wasdissolved in a mixture of water and dichloromethane. After theseparation of the organic phase the aqueous phase was further extractedwith dichloromethane. The organic phases were washed with water andbrine, dried with magnesium sulphate, filtered and the solvent wasremoved under reduced pressure affording 0.65 g of a deep-red oil. Aftertreatment with ethyl ether, 0.36 g (77% of yield) of a yellowish solidwere filtered off.

B. Preparation of3-(1-ethoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl)pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester

5.04 g (25.29 mmol) of3-(1,2,3,6-tetrahydropyridinyl)-1H-pyrrolo[2,3-b]pyridine were solved in45 ml of dichloromethane and 7.0 ml (50.59 mmol) of triethylamine wereadded to the solution. After cooling to 0° C., 5.0 ml (50.59 mmol) ofethyl chloroformate were added dropwise. The mixture was stirred at 0°C. for 6 hours and then washed with water and brine. The organic layerwas separated and dried with magnesium sulphate. After removing thesolvent under reduced pressure, 8.48 g (98% of yield) of an oil wereobtained which crystallized at room temperature.

C. Preparation of3-(1-ethoxycarbonyl-piperidin-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester

1.87 g of palladium, 10% (dry basis) on activated carbon (50% in water)were added over a solution of 8-48 g (24.7 mmol) of3-(1-ethoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl)pyrrolo[2,3-b]pyridine-1-carboxylic acid ethyl ester in 250 ml methanoland this mixture was hydrogenated at 2 bar for 20 hours. After filteringthrough Celite and removing the solvent under reduced pressure, 7.27 g(85% of yield) of the expected product were obtained.

D. Preparation of 3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

14.67 g (42.0 mmol) of3-(1-ethoxycarbonyl-piperidin-4-yl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester were added to a solution of 40.32 g (720 mmol) ofpotassium hydroxide in 630 ml of isopropanol. The mixture was refluxedfor 20 hours. The solvent was distilled off and cold water was added.This solution was acidified with concentrated hydrochloric acid and thenbasified with 8 N aqueous sodium hydroxide solution. This aqueoussolution was extracted twice with ethyl acetate. The organic phase waswashed with water and brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure affording 4.66 g (48% of yield) of theexpected product as an oil.

E. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethylester

4.66 g (20.0 mmol) of 3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine weresolved in 34 ml of dichloromethane and 3.1 ml (22.0 mmol) oftriethylamine were added to the solution. After cooling to 0° C., 2.2 ml(22.0 mmol) of ethyl chloroformate were added dropwise. The mixture wasstirred at 0° C. for 6 hours and then washed with water and brine. Theorganic layer was separated and dried with magnesium sulphate. Afterremoving the solvent under reduced pressure, 5.33 g of an oil wereobtained, which was purified by flash chromatography over silica gel.3.23 g (59% of yield) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1carboxylic acid ethyl ester were isolated.

F. Preparation of4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester

1.0 g (3.66 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethylester were dissolved in 10 ml of DMF and, at room temperature, 0.19 g(4.76 mmol) of 60% sodium hydride were carefully added. This mixture wasstirred for half an hour. 0.45 ml (5.12 mmol) of 1-bromo-2-methoxyethanewere added dropwise and the mixture was further stirred for 24 hours at60° C. The reaction mixture was cooled to room temperature and pouredover cold water. The aqueous phase was extracted twice withdichloromethane and the organic phase was washed with water and brine,dried with magnesium sulphate, filtered and evaporated to dryness. Thisresulted in 0.86 g (71% of yield) of product.

NMR (300 MHz, CDCl3) δ=1.18-1.38 (t, 3H), 1.58-1.72 (m, 2H), 1.95-2.10(m, 2H), 2.80-3.10 (m, 3H), 3.30 (s, 3H), 3.62-3.80 (t, 2H), 4.10-4.38(m, 4H), 4.39-4.42 (t, 2H), 6.90-7.15 (m, 2H), 7.85-7.95 (d, 1H),8.25-8.35 (m, 1H).

G. Preparation of1-(2-methoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

0.86 g (2.59 mmol) of4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester were added to a solution of 1.71 g (25.9 mmol) ofpotassium hydroxide in 25 ml of isopropanol. The mixture was refluxedfor 20 hours. The solvent was distilled off and cold water was added.This solution was acidified with concentrated hydrochloric acid and thenbasified with 8 N aqueous sodium hydroxide solution. This aqueoussolution was extracted twice with ethyl acetate. The organic phase waswashed with water and brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure. 0.42 g (68% of yield) of the expectedproduct were obtained as an oil.

H. Preparation of3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicadd methyl ester

0.42 g (1.62 mmol) of1-(2-methoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.45 g(1.94 mmol) of 3-bromomethylbenzoic acid methyl ester were solved in 9ml of 4-methyl-2-butanone and 0.67 g (4.86 mmol) of potassium carbonateand 0.02 g (0.16 mmol) of sodium iodide were added. The mixture wasrefluxed for 18 hours and, after cooling, water was added, the organiclayer separated and washed with water and brine. The solvent wasdistilled off. The crude material weighed 0.67 g and was used in thefollowing step without further purification.

I. Preparation of3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoicacid

0.66 g (1.62 mmol) of3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicacid methyl ester were dissolved in 0.8 ml of ethyl alcohol and 2.43 mlof 2 N sodium hydroxide were added. After stirring at room temperaturefor 20 hours, the solvent was evaporated under reduced pressure and theresidue dissolved in water. The mixture was neutralised with 2 Nhydrochloric acid and extracted twice with dichlormethane. The organicphase was washed with water and brine, dried with magnesium sulphate,fitrated and evaporated. The crude material weighed 0.46 g and waspurified by flash chromatography over silica gel affording 0.2 g (31% ofyield) of the expected product.

Melting point=154.9-156.3° C.

NMR (300 MHz, DMSO-d6) δ=1.67-1.71 (m, 2H), 1.91-1.95 (d, 2H), 2.15 (t,2H), 2.70-2.80 (t, 1H), 3.23 (s, 3H), 3.35-3.37 (m, 2H), 3.59 (s, 3H),3.66-3.70 (t, 2H), 4.33-4.37 (t, 2H), 7.01-7.06 (m, 1H), 7.32 (s, 1H),7.44-7.49 (m, 1H), 7.57-7.59 (m, 1H), 7.83-7.85 (m, 1H), 7.93 (s, 1H),7.98-8.01 (m, 1H), 8.19-8.21 (m, 1H).

EXAMPLE 2 Preparation of3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoicacid A. Preparation of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example1, part F, starting with 1.22 g (4.46 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethylester and 6.3 ml (6.24 mmol) of a freshly prepared 1 M solution of3-bromomethylfuran in ethyl ether. The crude mixture was stirred at 60°C. for 3 hours. After standard work-up, 1 g (63% of yield) of theexpected product was isolated.

B. Preparation of1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example1, part G, starting with 1 g (2.83 mmol) of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester. After standard work-up, 0.82 g(100% of yield) of the expected product were isolated.

NMR (300 MHz, CDCl₃) δ=1.50-1.68 (m, 2H), 1.82-2.10 (m, 2H), 2.65-2.99(m, 3H), 3.05-3.25 (m, 2H), 5.27 (s, 2H), 6.30 (s, 1H), 6.95 (s, 1H),6.96-7.15 (m, 1H), 7.30-7.42 (m, 2H), 7.95-8.00 (d, 1H), 8.20-8.40 (m,1H).

C. Preparation of3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-benzoicacid methyl ester

0.3 ml of triethylamine were added over a solution of 0.4 g (1.42 mmol)of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine in 5 mlof dichloromethane. A solution of 0.39 g (1.71 mmol) of3-bromomethyl-benzoic acid methyl ester in 2 ml of dichloromethane wasadded and the crude mixture was stirred at room temperature for 18hours. The mixture was diluted with 25 ml of dichloromethane and it waswashed with water and brine. The organic phase was dried over magnesiumsulphate and after filtration and evaporation, 0.53 g of the cruderesidue were obtained. The crude mixture was purified by flashchromatography over silica gel affording 0.3 g (49% of yield) of theexpected product.

NMR (300 MHz, CDCl₃) δ=1.70-1.99 (m, 4H), 2.05-2.25 (m, 2H), 2.60-2.90(m, 1H), 2.92-3.10 (m, 2H), 3.60 (s, 2H), 3.98 (s, 3H), 5.22 (s, 2H),6.25 (s, 1H), 6.90-7.12 (m, 2H), 7.30-7.42 (m, 3H), 7.70-7.81 (d, 1H),7.80-8.15 (m, 3H), 8.22-8.28 (d, 1H).

D. Preparation of3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoicacid

This compound was prepared following the procedure described in example1, part I, starting with 0.22 g (0.51 mmol) of3-[(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoicacid methyl ester. After standard work-up, 0.17 g (81% of yield) of theexpected product were obtained.

Melting point=1.77.0-178.8° C.

NMR (300 MHz, DMSO-d₆) δ=1.61-1.73 (m, 2H), 1.89-1.92 (m, 2H), 2.13 (t,2H), 2.72-2.79 (t, 1H), 2.87-2.91 (d, 2H), 3.33-3.35 (m, 2H), 3.57 (s,3H), 5.22 (s, 2H), 6.42 (s, 1H), 7.02-7.06 (m, 1H), 7.34 (s, 1H),7.41-7.47 (m, 1H), 7.55-7.57 (m, 2H), 7.63 (s, 1H), 7.81-7.84 (d, 1H),7.91 (s, 1H), 7.98-8.00 (d, 1H), 8.21-8.23 (m, 1H).

EXAMPLE 3 Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-yl]ethoxy}benzoicacid A. Preparation of2-(2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid methyl ester

This compound was prepared following the procedure described in example1, part H, starting with 0.28 g (1 mmol) of1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.26 g(1.2 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. Afterstandard work-up and purification, 0.16 g (35% of yield) of the expectedproduct were obtained.

B. Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-yl]ethoxy}benzoicacid

This compound was prepared following the procedure described in example1, part I, starting with 0.16 g (0.35 mmol) of 2-{2-[4(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-benzoicacid methyl ester. After standard work-up, 0.12 g (77% of yield) of theexpected product were obtained.

Melting point=105.2-106.8° C. NMR (300 MHz, DMSO-d₆) δ=1.97 (m, 4H),2.62 (m, 2H), 2.91 (m, 1H), 2.97 (m, 2H), 3.20-3.24 (d, 2H), 4.44 (m,3H), 5.26 (s, 2H), 6.45 (s, 1H), 6.99-7.10 (m, 2H), 7.22-7.25 (d, 1H),7.36 (s, 1H), 7.39-7.42 (m, 1H), 7.53-7.56 (d, 1H), 7.58 (s, 1H), 7.67(s, 1H) 8.16-8.18 (d, 1H), 8.26-8.27 (m, 1H).

EXAMPLE 4 Preparation of3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoicacid A. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

4.37 g (21.93 mmol) of3-(1,2,3,6-tetrahydro-pyridinyl)-1H-pyrrolo[2,3-b]pyridine were solvedin 40 ml of dichloromethane and 3.34 ml (24.12 mmol) of triethylaminewere added to the solution. After cooling at 0° C., 2.3 ml (24.12 mmol)of ethyl chloroformate were added dropwise. The mixture was stirred at0° C. for 6 hours and then washed with water and brine. The organiclayer was separated and dried with magnesium sulphate. After removingthe solvent under reduced pressure, 5.5 g of an oil were obtained whichwas purified by flash chromatography over silica gel. 1.96 g (33% ofyield) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester were isolated.

B. Preparation of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

1.30 g (4.76 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester were dissolved in 11 ml of DMF and, at roomtemperature, 0.25 g (5.6 mmol) of 60% sodium hydride were carefullyadded. This mixture was stirred for half an hour at room temperature.0.75 ml (6.0 mmol) of 2-bromoethyl ethyl ether were dropwise added andthe stirring was continued for 24 hours at 60° C. The reaction mixturewas cooled to room temperature and poured over cold water. This aqueousphase was extracted twice with dichloromethane and the organic phase waswashed with water and brine, dried with magnesium sulphate, filtered andevaporated to dryness. The 1.46 g (74% of yield) of crude material werepure enough for the next synthetic step.

C. Preparation of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester

0.19 g of palladium, 10% (dry basis) on activated carbon (50% in water)were added to a solution of 1.46 g (4.25 mmol) of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester in 40 ml methanol and this mixture was hydrogenated at2 bar for 6 hours. After filtering through celite and removing thesolvent under reduced pressure, 0.81 g (55% of yield) of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester were obtained. NMR (300 MHz, CDCl₃) δ=1.05-1.38 (m,6H), 1.55-2.12 (m, 5H), 2.90-3.05 (m, 2H), 3.20-3.50 (m, 4H), 3.60-3.65(m, 2H), 4.03-4.26 (m, 2H), 4.30-4.45 (m, 2H), 6.97-7.26 (m, 2H),7.90-8.03 (m, 1H), 8.22-8.27 (m, 1H).

D. Preparation of1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

1.1 g (3.18 mmol) of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester were added to a solution of 2.1 g (31.8 mmol) ofpotassium hydroxide in 30 ml of isopropanol. The mixture was refluxedfor 20 hours. The solvent was distilled off and cold water was added.This solution was acidified with concentrated hydrochloric acid and thenbasified with 8 N aqueous sodium hydroxide solution. This aqueoussolution was extracted twice with ethyl acetate. The organic phase waswashed with water and brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure affording 0.65 g (75% of yield) of1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine obtained as anoil.

E. Preparation of3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicacid methyl ester

0.98 g (3.58 mmol) of1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 0.92 g(4.29 mmol) of methyl 2-(2-chloroethoxy)benzoate were dissolved in 21 mlof 4-methyl-2-butanone and 1.48 g (10.74 mmol) of potassium carbonateand 0.07 g (0.4 mmol) of sodium iodide were added. The mixture wasrefluxed for 18 hours and, after cooling, water was added, the organiclayer separated, washed with water and brine. The solvent was distilledoff. The crude material weighed 2.1 g and was purified by flashchromatography over silica gel affording 0.58 g (36% of yield) of theexpected product.

F. Preparation of3{-([1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoicacid

0.58 g (1.28 mmol) of3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicadd methyl ester were dissolved in 5 ml of ethyl alcohol and 1.93 ml of2 N sodium hydroxide were added. After stirring at room temperature for20 hours, the solvent was evaporated under reduced pressure and theresidue dissolved in water. The mixture was neutralised with 2 Nhydrochloric acid and extracted twice with dichloromethane. The organicphase was washed with water and brine, dried with magnesium sulphate,filtrated and evaporated. The crude material weighed 0.65 g and waspurified by flash chromatography over silica gel affording 0.3 g (54% ofyield) of the expected product.

Melting point=173.2-175.0° C.

NMR (300 MHz, DMSO-d₆) δ=1.05-1.09 (t, 3H), 2.07-2.22 (m, 4H), 3.02-3.12(m, 3H), 3.40-3.46 (q, 2H), 3.51-3.55 (m, 1H), 3.73-3.76 (m, 2H), 4.27(s, 2H), 4.37-4.39 (m, 2H), 7.05-7.09 (m, 1H), 7.30 (s, 1H), 7.48-7.53(t, 1H), 7.63-7.65 (d, 1H), 8.04-8.10 (m, 2H), 8.19-8.21 (m, 2H).

EXAMPLE 5 Preparation of5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl}-2-methoxybenzoicacid A. Preparation of5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester

This compound was prepared following the procedure described in example4, part E, starting with 0.73 g (2.67 mmol) of1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.88 g(3.20 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. Afterstandard work-up and purification, 0.38 g (31% of yield) of the expectedproduct were obtained.

NMR (300 MHz, CDCl₃) δ=0.99-1.14 (t, 3H), 1.21-1.28 (t, 3H), 1.60-2.15(m, 4H), 2.58-2.79 (m, 1H), 2.80-2.99 (m, 2H), 3.22-3.45 (m, 4H),3.55-3.62 (m, 2H), 3.78 (s, 3H), 4.20-4.38 (m, 4H), 5.18 (s, 2H),6.78-7.00 (m, 3H), 7.35-7.41 (m, 1H), 7.62 (s, 1H), 7.78-7.82 (m, 1H),8.18-8.20 (m, 1H).

B.5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl}-2-methoxybenzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 0.38 g (0.52 mmol) of 5(4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester. After standard work-up, 0.22 g (62% of yield) of theexpected product were obtained.

Melting point=207.9-209.2° C.

NMR (300 MHz, DMSO-d₆) δ=1.02-1.07 (t, 3H), 1.17-1.23 (m, 2H), 1.73-1.77(m, 2H), 1.96-1.99 (m, 2H), 2.20-2.40 (m, ₁H), 2.83 (m, 1H), 3.02 (m,2H), 3.37-3.44 (m, 4H), 3.68-3.72 (t, 2H), 3.82 (s, 3H), 4.34-4.36 (m,2H), 7.02-7.06 (m, 1H), 7.13-7.15 (d, 1H), 7.33 (s, 1H), 7.50-7.52 (d,1H), 7.66 (s, 1H), 7.99-8.03 (d, 1H), 8.20-8.21 (m, 1H).

EXAMPLE 6 Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylethoxy)benzoicacid A. Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 0.98 g (3.58 mmol) of1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.92 g(4.29 mmol) of 2-(2-chloroethoxy)benzoic acid methyl ester. Afterstandard work-up and purification, 0.58 g (36% of yield) of the expectedproduct were obtained.

B.2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylethoxy)benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 0.58 g (1.28 mmol) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoicadd methyl ester. After standard work-up, 0.3 g (54% of yield) of theexpected product were obtained.

Melting point=136.6-140.3° C.

NMR (300 MHz, DMSO-d6) δ=1.03-1.08 (t, 3H), 1.97-2.45 (m, 4H), 2.59-2.68(m, 2H), 2.89-2.99 (m, 3H), 3.21-3.24 (d, 2H), 3.37-3.46 (q, 2H),3.70-3.73 (t, 2H), 4.34-4.38 (t, 2H), 4.42-4.46 (m, 2H), 5.20-6.20 (m,1H), 6.99-7.08 (m, 2H), 7.22-7.25 (d, 1H), 7.34 (s, 1H), 7.37-7.42 (m,1H), 7.53-7.56 (d, 1H), 8.14-8.17 (d, 1H), 8.23-8.24 (d, 1H).

Alternatively, the novel azaindolylpiperidine derivatives of the presentinvention can be prepared according to a different strategy as shown inScheme 3.

A condensation between a compound of general formula II wherein A, B. D,E and R₄ are as defined above and a compound of general formula XVwherein R₅ and q are as defined above and R₆ is an ethyl or tert-butylgroup gives a compound of general formula XVI. This reaction ispreferably carried out in the presence of a base such as sodium orpotassium hydroxide in an alcoholic solvent such as methanol, ethanol orisopropanol at a temperature between 600 and 150° C.

The compound of general formula XVI, wherein A, B, D, E, R₄, R₅ and qare as defined above and R₈ is a tert-butyl group, is treated with ethylchloroformate in the presence of a base such as triethylamine at atemperature between 0° C. and 80° C. to give a compound of generalformula XVII wherein A, B, D, E, R₄, R₅ and q are as defined above andR₈ is a tert-butyl group.

Compound XVII is either hydrogenated using palladium or platinum oxideas catalyst in a solvent such as methanol or ethanol in acidic orneutral conditions at a pressure between 2 or 3 bar or reduced with anhydride such as sodium borohydride to give a compound of general formulaXVIII wherein A, B, D, E, R₄, R₅ and q are as defined above and R₆ is atert-butyl group.

The ethyl carbamate moiety on the indolyl group is deprotected byboiling compound XVIII in the presence of an excess of sodium orpotassium hydroxide in an alcoholic solvent such as ethanol orisopropanol at a temperature between 80° C. and 180° C., giving acompound of general formula XIX wherein A, B, D, E, R₄, R₅ and q are asdefined above and R₆ is a tert-butyl group.

Alternatively, the compound of general formula XVI wherein A, B, D, E,R₄, R₅ and q are as defined above and R₆ is an ethyl group is eitherhydrogenated using palladium or platinum oxide as catalyst in a solventsuch as methanol or ethanol in acidic or neutral conditions at apressure between 2 or 3 bar or reduced using an hydride such as sodiumborohydride, to give a compound of general formula XIX wherein A, B, D,E, R₄, R₅ and q are as defined before and R₆ is an ethyl group.

The compound of general formula XIX wherein R₆ is either an ethyl or atert-butyl group is alkylated with a reactive intermediate of generalformula VIII, which is as previously defined in Scheme 1, to give acompound of general formula XX wherein A, B, D, E, R₂, R₄, R₅ and q areas defined above, and R₆ is an ethyl or a tert-butyl group. Thisreaction is preferably carried out in an inert solvent such astetrahydrofuran, dimethylformamide or ethyl ether in the presence of aninorganic base such as sodium hydride or sodium amide at a temperaturebetween 0° C. and 80° C.

The compound of general formula XX is deprotected to give a compound offormula X, which is as previously defined in Scheme I. When thesubstituent R₈ of compound XX is a tert-butyl group this is done bytreatment with trifluoroacetic acid in dichloromethane at a temperaturebetween 0° C. and room temperature. When the substituent R₈ of compoundXX is an ethyl group it is deprotected by treatment with sodium orpotassium hydroxide in a solvent such as ethanol, isopropanol orn-butanol at a temperature between 80° C. and 180° C.

As in Scheme I, the alkylation of compound X with a reactiveintermediate of general formula XI gives a compound of general formulaI. This reaction is preferably carried out in an organic solvent such astoluene, dichloromethane, dioxane or methyl isobutylketone at atemperature between 25° C. and 140° C. and in the presence of a basesuch as an alkali metal carbonate or bicarbonate, triethylamine ordiisopropylethylamine.

Compounds of general formula I wherein R₇ is an oxygen atom are treatedwith sodium or potassium hydroxide in a solvent such as methanol,ethanol or tetrahydrofuran at a temperature between 25° C. and 60° C.Further treatment with an inorganic acid such as hydrochloric acidprovides the corresponding azaindolylpiperidine derivatives of generalformula XIV wherein A, B. D, E, L₁, L₂, R₂, R₄, R₅, q, W₁, n and X areas defined above (see Scheme 2).

The following Examples represent typical synthetic procedures accordingto Scheme 3. These Examples are given by way of illustration only andare not intended to limit the scope of the present invention in any way.TABLE 2 List of examples according to Scheme 3

Example R1 R2 Mol. weight 7

445.516 8

445,516 9

415,516 10

445,516 11

461.583 12

431.558 13

461.583 14

461.583 15

431.558 16

461.583 17

496.003 18

466.003 19

496.003 20

423.510 21

423.510 22

453.536 23

453.536 24

421.538 25

421.538 28

391.512 27

419.522 28

389.496 29

419.522 30

407.511 31

377.485 32

407.511 33

473.545 34

395.475 35

411.474 36

467.563 37

467.563 38

471.982 39

425.501 40

437.537 41

467.563 42

467.563 43

475.542 44

479.961 45

433.481 46

475.542 47

445.516 48

475.542 49

475.542 50

475.542 51

475.542 52

479.961 53

433.481 54

526.054 55

526.054 56

530.474 57

483.993 58

496.028 59

526.054 60

526.054 61

451.564 62

451.564 63

455.983 64

409.502 65

421.538 66

451.564 67

451.564 68

456.543 69

378.473 70

437.537 71

467.563 72

467.563 73

471.982 74

437.537 75

486.407 76

475.542 77

445.516 78

445.516 79

445.516 80

479.961 81

421.538 82

451.564 83

451.564 84

455.983 85

421.538 86

470.408 87

391.512 88

496.028 89

496.028 90

526.054 91

526.054 92

530.474 93

433.958 94

461.583 95

445.516 96

445.516 97

491.609 98

461.583 99

423.510The sign (*) in the structures shows the point of attachment. It doesnot symbolise a carbon atom.

EXAMPLE 7 Preparation of5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid A. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

5 g (40 mmol) of 7-azaindole and 20 g (100 mmol)4-oxopiperidine-1-carboxylic acid tert-butyl ester were added to anice-cooled solution of 6 g (100 mmol) of potassium hydroxide in 120 mlof methanol. The mixture was heated to room temperature and thenrefluxed for 18 hours. Once cooled to room temperature, the formed solidwas isolated by suction filtration. The filtered solution wasconcentrated at vacuum and a mixture of 22 ml of ethanol and 50 ml ofwater was added to the residue. A yellowish solid precipitated whichcorresponded to 6.32 g (53% of yield) of the expected product.

B. Preparation of3-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester

Over a solution of 6.3 g (21.07 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester and 3.2 ml (23.16 mmol) of triethylamine in 50 mlof dichloromethane at 0° C., 2.2 ml (23.16 mmol) of ethyl chloroformatewere added dropwise. The crude mixture was stirred at 0° C. for 1 hourand then warmed to room temperature for 8 hours. The reaction mixturewas washed with 50 ml of water and the organic phase was separated.After drying over sodium sulphate, filtering and removing the solvent atreduced pressure, 8.7 g (100% of yield) of3-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester were isolated.

C. Preparation of3-(1-tert-butoxycarbonyl-piperidin-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester

0.47 g of palladium, 10% (dry basis) on activated carbon were added to asolution of 4.67 g (12.6 mmol) of3-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl)-pyrrolo[2,3-b]pyridine-1-carboxylicadd ethyl ester in 150 ml of methanol and this mixture was submitted tohydrogenation at 30 psi for 24 hours. After filtering through celite andremoving the solvent under reduced pressure, 4 g (85% of yield) of theexpected product were obtained.

D. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-rboxylic acid tert-butylester

4 g (10.72 mmol) of3-(1-tert-butoxycarbonyl-piperidin-4-yl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid ethyl ester were added to a solution of 3 g (53.6 mmol) ofpotassium hydroxide in 120 ml of isopropanol. The mixture was refluxedfor 16 hours. The solvent was distilled off and cold water was added.This solution was acidified with concentrated hydrochloric acid and thenbasified with 8 N aqueous sodium hydroxide solution. This aqueoussolution was extracted twice with ethyl acetate. The organic phase waswashed with water and brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure. 1.6 g (50% of yield) of the expectedproduct were obtained as yellowish solid.

E. Preparation of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylicacid tert-butyl ester

Under nitrogen atmosphere, 1.14 g (3.76 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester were dissolved in 30 ml of anhydrous DMF and, at roomtemperature, carefully added to a suspension containing 0.24 g (6.05mmol) of 60% sodium hydride. This mixture was stirred for 30 minutes and8.2 ml (4.92 mmol) of a freshly prepared 0.6 M solution of3-bromomethylfuran in ethyl ether were dropwise added and the reactionmixture was stirred at room temperature for 16 hours. The solvent wasremoved under reduced pressure and the crude mixture was extractedbetween ethyl acetate and water. The organic phase was washed with waterand brine, dried with magnesium sulphate, filtered and evaporated todryness. The crude mixture was purified by flash chromatography oversilica gel affording 1.4 g (97% of yield) of the expected product.

F. Preparation of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

Over a solution of 1.4 g (3.7 mmol) of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester in 10 ml ofdichloromethane, 2.85 ml of trifluoroacetic acid were carefully added.The crude mixture was stirred at room temperature for 1 hour. Thesolvent was removed under reduced pressure and the crude residue wasdissolved in 10 ml of ethyl acetate and washed with saturated aqueoussolution of sodium carbonate and brine. After drying over sodiumsulphate, filtering and removing the solvent under reduced pressure,0.62 g (60% of yield) of the expected product were obtained.

NMR (300 MHz, CDCl3) δ=1.50-1.68 (m, 2H), 1.82-2.10 (m, 2H), 2.65-2.99(m, 3H), 3.05-3.25 (m, 2H), 5.27 (s, 2H), 6.30 (s, 1H), 6.95 (s, 1H),6.96-7.15 (m, 1H), 7.30-7.42 (m, 2H), 7.95-8.00 (d, 1H), 8.20-8.40 (m,1H).

G. Preparation of 5-[4-(1-furan-3-ylmethyl-1Hpyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acidethyl ester

This compound was prepared following the procedure described in example4, part E, starting with 0.62 g (2.2 mmol) of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 0.79 g(2.9 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. Afterstandard work-up and purification, 0.95 g (91% of yield) of the expectedester were obtained.

NMR (300 MHz, CDCl₃) δ=1.35-1.42 (t, 3H), 1.80-2.15 (m, 6H), 2.70-3.15(m, 3H), 3.55 (s, 2H), 3.98 (s, 3H), 4.30-4.40 (q, 2H), 5.23 (s, 2H),6.92-7.30 (m, 5H), 7.35-7.45 (m, 3H), 7.70 (s, 1H), 7.90 (d, 1H), 8.30(d, 1H).

H. Preparation of5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 0.95 g (2 mmol) of5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid ethyl ester. After standard work-up, 0.7 g of the crude acid wereobtained which were washed with hot water, ethanol and ethyl etheraffording 0.33 g (37% of yield) of the pure acid.

Melting point=230.5-232.4° C.

NMR (300 MHz, DMSO-d₆) δ=1.61-1.72 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15(t, 2H), 2.73-2.80 (m, 1H), 2.88-2.92 (d, 2H), 3.48 (s, 2H), 3.80 (s,3H), 5.23 (s, 2H), 6.43 (s, 1H), 7.03-7.09 (m, 2H), 7.34 (s, 1H),7.41-7.45 (dd, 1H), 7.56-7.58 (m, 2H), 7.64 (s, 1H), 7.99-8.01 (d, 1H),8.23-8.24 (m, 1H).

EXAMPLES 8-9

These compounds were prepared following the procedure described inexample 7, parts G and H, starting with 0.094 g (0.33 mmol) of1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 3.

A. Preparation of1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example7, parts E and F, starting with 0.3 g (1 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of2-bromomethylfuran in ethyl ether. After standard work-up, 0.28 g (97%of yield) of the expected product were isolated. TABLE 3 Example ESI/MSm/e [(M)+] Purity (%) 8 445 100 9 415 100

EXAMPLE 10 Preparation of5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxybenzoicacid

This compound was prepared following the procedure described in example7, part G and H starting with 2.37 g (8.4 mmol) of1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 3 g(11 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. Afterstandard purification the overall yield was 76% (1.6 g).

Melting point=230.9-231.8° C.

NMR (300 MHz, DMSO-d₆) δ=1.61-1.73 (m, 2H), 1.89-1.93 (d, 2H), 2.09-2.16(t, 2H), 2.73-2.81 (t, 1H), 2.89-2.92 (d, 2H), 3.49 (s, 2H), 3.80 (s,3H), 5.40 (s, 2H), 6.36-6.39 (m, 2H), 7.04-7.08 (dd, 1H), 7.30 (s, 1H),7.41-7.44 (dd, 1H), 7.56-7.58 (m, 2H), 8.00-8.03 (m, 1H), 8.23-8.25 (dd,1H)

EXAMPLES 11-13

These compounds were prepared following the procedure described inexample 7, parts G and H, starting with 0.098 g (0.33 mmol) of3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine. Thecrude mixtures were purified by preparative HPLC triggered by MS. ESI/MSdata corresponding to these compounds are shown in table 4.

A. Preparation of3-piperidinyl-1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example7, parts E and F, starting with 0.3 g (1 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butylester and 2.12 ml of a freshly prepared 0.61 M solution of2-bromomethylthiophene in ethyl ether. After standard work-up, 0.29 g(100% of yield) of the expected product were isolated. TABLE 4 ExampleESI/MS m/e [(M)+] Purity (%) 11 461 100 12 431 51 13 461 100

EXAMPLES 14-16

These compounds were prepared following the procedure described inexample 7, parts G and H, starting with 0.098 g (0.33 mmol) of3-piperidinyl-1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 5.

A. Preparation of3-piperidinyl-1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example7, parts E and F, starting with 0.3 g (1 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of3-bromomethylthiophene in ethyl ether. After standard work-up, 0.39 g(100% of yield) of the expected product were isolated. TABLE 5 ExampleESI/MS m/e [(M)+] Purity (%) 14 461 100 15 431 100 16 461 100

EXAMPLE 17 Preparation of2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoicacid A. Preparation of4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

This compound was prepared following the procedure described in example7, part E, starting with 2 g (6.6 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester and 0.94 ml (8 mmol) of2-chloro-5-(chloromethyl)thiophen. After standard work-up andpurification, 2.86 g of4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicadd tert-butyl ester were obtained.

B. Preparation of1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

Over a solution of 2.86 g (6.6 mmol) of4-[1-(5-chlorothiophen-2-ylmethyly)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid tert-butyl ester in 20 ml of dichloromethane, 5.1 ml oftrifluoroacetic acid were added. After 1 hour at room temperature, thesolvent was removed under reduced pressure. The crude mixture wasdissolved in ethyl acetate and washed with saturated solution ofpotassium carbonate and brine. The organic phase was dried overmagnesium sulphate, filtered and removed under reduced pressureaffording 2.8 g of a crude mixture which was pure enough for the nextsynthetic step.

C. Preparation of2-(2-(4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E starting with 2.8 g (6.5 mmol) of1-(5-chloro-thiophen-2-ylmethyl)₃-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridineand 1.5 g (7.2 mmol) of methyl 2-(2-chloroethoxy)benzoate. Afterstandard work-up and purification, 1.1 g (33% yield) of2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoicacid methyl ester were obtained.

D. Preparation of2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoicacid

This compound was prepared following the procedure described in example4, part F starting with 1.1 g (2.2 mmol) of2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoicacid methyl ester. After standard work-up and purification, 0.38 g (35%yield) were obtained.

Melting point=149.9-151.3° C.

NMR (300 MHz, DMSO-d6) δ=1.80-2.01 (m, 4H), 2.50-2.72 (m, 2H), 2.88-3.12(m, 3H), 3.20-3.24 (m, 2H), 4.43 (m, 2H), 5.54 (s, 2H), 6.96-7.04 (m,4H), 7.08-7.12 (t, 1H), 7.22-7.24 (d, 1H), 7.37-7.42 (m, 2H), 7.54-7.56(d, 1H), 8.16-8.19 (d, 1H), 8.28-8.29 (d, 1H)

EXAMPLE 18

This compound was prepared following the procedure described in example17, parts C and D, starting with 0.098 g (0.33 mmol) of1-(S-chloro-thiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine.The crude mixture was purified by preparative HPLC triggered by MS.

EXAMPLE 19 Preparation of5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 2.8 g (5.35 mmol) of5-{4-[1-(5-chloro-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester. After standard work-up, 2 g (75% of yield) of theexpected acid were obtained.

Melting point=200.9-202.0° C.

NMR (300 MHz, DMSO-d₆) δ=1.63-1.69 (m, 2H), 1.90-1.95 (m, 2H), 2.72-2.78(m, 1H), 2.89-2.93 (d, 2H), 3.51 (s, 2H), 3.81 (s, 3H), 5.51 (s, 2H),6.94-6.98 (m, 2H), 7.06-7.10 (m, 2H), 7.40-7.46 (m, 2H), 7.59 (s, 1H),8.01-8.04 (d, 1H), 8.25-8.26 (d, 1H).

EXAMPLES 20-23

These compounds were prepared following the procedure described inexample 7, parts G and H, starting with 0.082 g (0.32 mmol) of1-(2-methoxyethyl)₃-piperidinyl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 6.

A. Preparation of1-(2-methoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example7, parts E and F, starting with 0.2 g (0.66 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester and 0.081 ml (0.864 mmol) of 1-bromo-2-methoxyethane.After standard work-up, 0.15 g (100% of yield) of the expected productwere isolated. TABLE 6 Example ESI/MS m/e [(M)+] Purity (%) 20 423 10021 423 98 22 453 99 23 453 96

EXAMPLE 24 Preparation of5-{4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoicacid A. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

A suspension 5.51 g (0.05 mol) of 7-azaindol, 9.6 g (0.056 mol) of4-oxo-piperidine-1-carboxylic acid ethyl ester and 5 g (0.075 mol) ofpotassium hydroxide in 120 ml of methanol was heated at 75° C. for 16hours. The crude mixture was cooled at room temperature and theprecipitate formed was filtered off. 7.8 g (57% of yield) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester were obtained.

B. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester

7.8 g (0.029 mol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester were dissolved in 250 ml of ethanol and 7.8 g ofpalladium over carbon at 10% were added. The crude mixture washydrogenated at 30 psi for 24 hours. After filtering the catalyst andremoval of the solvent at reduced pressure, 4.95 g (62% of yield) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester were obtained.

C. Preparation of4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-carboxylic acidethyl ester

Under nitrogen atmosphere, over a suspension of 0.55 g (13.72 mmol) ofsodium hydride 60% in parafin oil in 10 ml of DMF, a solution of 2.5 g(9.1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylicacid ethyl ester in 10 ml of DMF was added. After 30 minutes, a solutionof 1.2 ml of 4-bromobutane in 2 ml of DMF was added. The crude mixturewas stirred at room temperature for 15 hours. The solvent was removedunder reduced pressure and the crude was partionated between ethylacetate and water. The organic phase was dried over sodium sulphate,filtered and the solvent was removed under reduced pressure affording3.1 g of4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidethyl ester.

D. Preparation of 1-butyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example4, part D, starting with 3.1 g (9.1 mmol) of41-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acidethyl ester. After standard work-up, 2.23 g (95% yield) of1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine were obtained.

E. Preparation of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid methyl ester

Over a solution of 2.2 g (8.66 mmol) of1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine in 40 ml ofdichloromethane, 1.66 ml (9.52 mmol) of DIEA were added. Over the crudemixture, a solution of 2.6 g (9.5 mmol) of5-bromomethyl-2-methoxy-benzoic acid ethyl ester in 5 ml ofdichloromethane was carefully added. The crude mixture was stirred atroom temperature for 16 hours and it was diluted with 50 ml ofdichloromethane. The organic phase was washed with bicarbonate aqueoussolution and brine. It was dried over sodium sulphate, filtered and thesolvent removed under reduced pressure. The crude mixture was purifiedby chromatography over silica gel affording 2.9 g (77% yield) of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid methyl ester were obtained.

F. Preparation of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 1.45 g (3.22 mmol) of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid methyl ester. After standard work-up and purification, 0.83 g (92%yield) of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid were obtained.

Melting point=243-0-244.2° C.

NMR (300 MHz, DMSO-d6) δ=0.85-0.90 (t, 3H), 1.19-1.27 (m, 2H), 1.64-1.80(m, 4H), 1.89-1.99 (m, 2H), 2.10-2.40 (m, 2H), 2.70-2.90 (m, 3H),3.59-3.62 (m, 2H), 3.81 (s, 3H), 4.16-4.21 (t, 2H), 7.00-7.04 (dd, 1H),7.08-7.11 (d, 1H), 7.33 (s, 1H), 7.42-7.49 (m, 1H), 7.58-7.63 (m, 1H),7.95-8.00 (m, 1H) 8.18-8.22 (m, 1H)

EXAMPLES 25-26

Example 25 was prepared following the procedure described in example 4(parts E and F) and example 26 was prepared following the proceduredescribed in example 24 (parts E and F) starting with 0.059 g (0.23mmol) of 1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 7. TABLE7 Example ESI/MS m/e [(M)+] Purity (%) 25 421 100 26 391 96

EXAMPLES 27-29

Example 27 was prepared following the procedure described in example 4(parts E and F) and example 28 and 29 were prepared following theprocedure described in example 24 (parts E and F), starting with 0.080 g(0.32 mmol) of1-cyclopropylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine. Thecrude mixtures were purified by preparative HPLC triggered by MS. ESI/MSand purity data corresponding to these compounds are shown in table 8.

A. Preparation of1-cyclopropylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, parts C and D, starting with 0.3 g (1 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 0.175 g (1.23 mmol) of bromomethylcyclopropane. After standardwork-up, 0.242 g (96% of yield) of the expected product were isolated.TABLE 8 Example ESI/MS m/e [(M)+] Purity (%) 27 419 100 28 389 100 29419 100

EXAMPLES 30-32

These compounds were prepared following the procedure described inexample 4, parts E and F, starting with 0.080 g (0.32 mmol) of1-isopropyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurirty data corresponding to these compounds are shown in table 9.

A. Preparation of 1-isopropyl-3-piperidin 4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, parts C and D, starting with 0.3 g (1 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl-piperidine-1-carboxylic acid ethylester and 0.159 g (1.23 mmol) of 2-bromopropane. After standard work-up,0.242 g (100% of yield) of the expected product were isolated. TABLE 9Example ESI/MS m/e [(M)+] Purity (%) 30 407 98 31 377 66 32 407 99

EXAMPLES 33-35

These compounds were prepared following the procedure described inexample 4, parts E and F, starting with 0.066 g (0.22 mmol) of1-(4-fluorobenzyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 10.

A. Preparation of1-(4-fluorobenzyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, parts C and D, starting with 0.2 g (0.66 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic add ethylester and 0.163 g (0.86 mmol) of 2-bromomethylpyridine. After standardwork-up, 0.21 g (68% of yield) of the expected product were isolated.TABLE 10 Example ESI/MS m/e [(M)+] Purity (%) 33 473 80 34 395 100 35411 82

EXAMPLE 36 Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoicacid A. Preparation of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 2.8 g (10 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 1.7 ml (15 mmol) of 2-bromoethylethyl ether. After standardwork-up and purification, 3.5 g of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester were obtained.

B. Preparation of1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, part D, starting with 3.5 g (10 mmol)4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester. After standard work-up, 3 g (84% yield) of1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine wereobtained.

C. Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 3 g (10.9 mmol) of1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-b]pyridine and 4 g (16.5mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. Afterstandard work-up and purification, 2.3 g (44% yield) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoicacid methyl ester were obtained.

D. Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 2.5 g (4.77 mmol) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoicacid methyl ester. After standard work-up and purification, 0.8 g (36%yield) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}ethoxy)-4-methoxy-benzoicacid were obtained.

Melting point=106.1-107.5° C.

NMR (300 MHz, DMSO-d6) δ=1.03-1.07 (t, 3H), 1.81-2.05 (m, 4H), 2.59-2.65(t, 2H), 2.81-3.01 (m, 3H), 3.26-3.29 (d, 2H), 3.38-3.45 (dd, 2H),3.69-3.73 (t, 2H), 3.82 (s, 3H), 4.34-4.41 (m, 4H), 6.61-6.64 (d, 1H),6.77 (m, 1H), 7.03-7.07 (dd, 1H), 7.33 (s, 1H), 7.64-7.67 (d, 1H),8.08-8.11 (d, 1H), 8.22-8.23 (d, 1H)

EXAMPLES 37-42

These compounds were prepared following the procedure described inexample 36. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 11. TABLE 11 Example ESI/MSm/e [(M)+] Purity (%) 37 467 100 38 471 91 39 425 100 40 437 95 41 46797 42 467 92

EXAMPLE 43 Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid A. Preparation of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

Over a solution of 28 g (0.42 mol) of potassium hydroxide in 300 ml ofethanol, a solutio of 20 g (0.17 mol) of 7-azaindol in 40 ml of ethanolwas added. Over the crude mixture, 32.1 ml (0.21 mol) of4-oxo-piperidine-1-carboxylic acid ethyl ester were added. The crudemixture was refluxed for 18 hours. It was partionated between ethylacetate and water. The organic phase was dried over sodium sulphate,filtered and the solvent was removed under reduced pressure. The residuewas crystallised with ethyl acetate affording 16 g (50% yield) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1 arboxylicacid ethyl ester.

B. Preparation of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1arboxylic acid ethyl ester

3.3 g (12 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester were dissolved in 15 ml of ethanol and 5 ml of THF.Over this solution, 3.3 g of Pd over carbon at 10% were added. The crudemixture was hydrogenated at 30 psi for 48 hours. The catalyst wasfiltered off and the solvent removed under reduced pressure affording1.55 g (54%) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester.

C. Preparation of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 3 g (11 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1 carboxylic acid ethylester and 20 ml of a 0.6M solution of 3-bromomethylfuran freshlyprepared. After standard work-up, 4.44 g of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-arboxylicacid ethyl ester were obtained.

D. Preparation of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, part D, starting with 4.44 g (11 mmol) of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester and 3.6 g of potassiumhydroxide. After standard work-up, 3.85 g of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine wereobtained.

E. Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 3.8 g (11 mmol) of1-furan-3-ylmethyl-3-piperidin yl-1H-pyrrolo[2,3-b]pyridine and 4.03 g(16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester.After standard work-up and purification, 2.5 g (50% yield) of22-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-ethoxy)-4-methoxy-benzoicacid methyl ester were obtained.

F. Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}4methoxy-benzoic acid

This compound was prepared following the procedure described in example4, part F, starting with 2.5 g (5.1 mmol) of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid methyl ester. After standard work-up and purification, 1.2 g (50%yield) of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}4-methoxybenzoicacid were obtained.

Melting point=91.5-93.2° C. NMR (300 MHz, DMSO-d6) δ=1.79-1.98 (m, 4H),2.40-2.48 (t, 2H), 2.76-2.93 (m, 3H); 3.23-315 (m, 2H), 3.81 (s, 3H),4.30-4.46 (m, 2H), 5.26 (s, 2H), 6.45 (s, 1H), 6.60-6.63 (m, 1H),6.77-6.79 (m, 1H), 7.05-7.09 (m, 1H), 7.34 (s, 1H), 7.57-7.66 (m. 2H),8.10-8.12 (dd, 1H), 8.35-8.27 (m, 1H)

EXAMPLE 44 Preparation of4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid

This compound was prepared following the procedure described in example4, parts E and F, starting with 1.5 g (5.3 mmol) of1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.7 g(6.9 mmol) of 2-(2-chloroethoxy)-4-chlorobenzoic acid methyl ester.After standard work-up and purification, 0.3 g (10% yield) of4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid were obtained.

Melting point=81.6-83.3° C.

NMR (300 MHz, DMSO-d₆)=1.88-2.14 (m, 4H), 2.70-2.77 (t, 2H), 2.87-2.96(m, 1H), 3.04-3.08 (t, 2H), 3.29-3.33 (m, 2H), 4.48-4.51 (t, 2H), 5.26(s, 2H), 6.45 (s, 1H), 7.05-7.10 (m, 2H), 7.33-7.38 (m, 2H), 7.52-7.58(m, 2H), 7.67 (s, 1H), 8.16-8.22 (dd, 1H), 8.26-8.28 (dd, 1H)

EXAMPLE 45-49

These compounds were prepared following the procedure described inexample 44. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 12. TABLE 12 Example ESI/MSm/e [(M)+] Purity (%) 45 433 100 46 475 99 47 445 88 48 475 91 49 475 85

EXAMPLE 50 Preparation of2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part E and F starting with 3.6 g (11 mmol) of1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 4.0 g(16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester.After standard purification the overall yield was 36% (1.93 g).

Melting point=186.9-1.89.2° C.

NMR (300 MHz, DMSO-d6) δ=1.93-2.09 (m, 4H), 2.47-2.54 (m, 2H), 2.76-3.01(m, 3H); 3.15-3.23 (m, 2H), 3.37-3.50 (m, 2H), 3.82 (s, 3H), 4.45 (m,2H), 5.43 (s, 2H), 6.40 (m, 2H), 6.62-6.65 (dd, 1H), 6.75-6.76 (m, 1H),7.07-7.11 (dd, 1H), 7.33 (s, 1H), 7.58 (s, 1H), 7.68-7.71 (d, 1H),8.13-8.15 (d, 1H), 8.26-8.27 (d, 1H)

EXAMPLES 51-53

These compounds were prepared following the procedure described inexample 50. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 13. TABLE 13 Example ESI/MSm/e [(M)+] Purity (%) 51 475 99 52 479 95 53 433 100

EXAMPLE 54 Preparation of2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part E and F starting with 2 g (6 mmol) of1-(5-chlorothiophen-2-ylmethyl)₃-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridineand 1.9 g (7.85 mmol) of 2-(2chloroethoxy)-3-methoxy-benzoic acid methylester. After standard purification the overall yield was 14% (0.8 g).

Melting point=110.7-112.6° C.

NMR (300 MHz, DMSO-d6) δ=1.90-2.14 (m, 4H), 2.70-2.80 (m, 2H), 2.90-3.11(m, 3H), 3.25-3.32 (m, 2H), 3.81 (s, 3H), 4.38-4.46 (d, 2H), 5.54 (s,2H), 6.93-7.15 (m, 6H), 7.44 (s, 1H), 8.21-8.24 (dd, 1H), 8.27-8.30 (dd,1H)

EXAMPLES 55-60

These compounds were prepared following the procedure described inexample 54. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 14. TABLE 14 Example ESI/MSm/e [(M)+] Purity (%) 55 526 88 56 530 92 57 483 99 58 496 70 59 526 7160 526 82

EXAMPLE 61 Preparation of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part E and F starting with 2.5 g (9.1 mmol) of1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 3.3 g (13.6 mmol) of2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standardpurification the overall yield was 35% (0.77 g).

Melting point=175-177° C.

NMR (300 MHz, DMSO-d6) δ=0.86-0.91 (t, 3H), 1.18-1.31 (m, 2H), 1.70-1.80(m, 2H), 1.92-2.10 (m, 4H), 2.75-3.00 (m, 3H), 3.13-3.23 (m, 2H),3.36-3.45 (m, 2H), 3.82 (s, 3H), 4.18-4.23 (t, 2H), 4.43-4.46 (t, 2H),6.62-6.66 (dd, 1H), 6.74-6.76 (d, 1H), 7.02-7.06 (dd, 1H), 7.35 (s, 1H),7.68-7.71 (d, 1H), 8.09-8.11 (m, 1H), 8.22-8.23 (m, 1H)

EXAMPLES 62-67

These compounds were prepared following the procedure described inexample 61. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 15. TABLE 15 Example ESI/MSm/e [(M)+] Purity (%) 62 451 95 63 455 99 64 409 99 65 421 97 66 451 10067 451 90

EXAMPLES 68-69

These compounds were prepared following the procedure described inexample 4, parts E and F, starting with 0.066 g (0.22 mmol) of3-piperidinyl-1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine. The crudemixtures were purified by preparative HPLC triggered by MS. ESI/MS andpurity data corresponding to these compounds are shown in table 16.

A. Preparation of3-piperidin-4-yl-1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine

This compound was prepared following the procedure described in example24, parts C and D, starting with 0.2 g (0.66 mmol) of4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 0.149 g (0.86 mmol) of 2-bromomethylpyridine. After standardwork-up, 0.21 g (72% of yield) of the expected product were isolated.TABLE 16 Example ESI/MS m/e [(M)+] Purity (%) 68 456 73 69 378 100

EXAMPLE 70 Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoicacid A. Preparation of4-(1H-pyrrolo[2,3c]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester

This compound was prepared following the procedure described in example24, parts A and B, starting with 3.1 g (26.24 mmol) of 6-azaindol and4.36 ml (28.86 mmol) of 1-carbethoxy-4-piperidona. After two syntheticsteps, 3.1 g (91% yield) were obtained.

B. Preparation of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 1.05 g (3.84 mmol) of4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 0.52 ml (4.61 mmol) of 2-bromoethylethyl ether. After standardwork-up and purification, 0.83 g (63% yield)4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester were obtained.

C. Preparation of1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3]pyridine

This compound was prepared following the procedure described in example24, part D, starting with 0.83 g (2.4 mmol) of4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester. After standard work-up, 0.46 g (71% yield) of1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine were obtained.

D. Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3c]pyridin-3-yl]-piperidin-1-yl}ethoxy)-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 0.46 g (1.7 mmol) of1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-c]pyridine and 0.44 g(2.0 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. Afterstandard work-up and purification, 0.2 g (21% yield) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoicacid methyl ester were obtained.

E. Preparation of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 0.21 g (0.46 mmol) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoicacid methyl ester. After standard work-up and purification, 0.18 g (90%yield) of5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxy-benzoicacid were obtained.

Melting point=173.8-175.1° C.

NMR (300 MHz, DMSO-d6) δ=0.99-1.05 (m, 3H), 2.05-2.09 (m, 2H), 2.20-2.30(m, 2H), 3.14-3.52 (m, 7H), 3.70-3.73 (t, 4H), 4.52-4.58 (m, 4H),7.04-7.09 (t, 1H), 7.20-7.23 (d, 1H), 7.52-7.57 (t, 1H), 7.67-7.70 (d,1H), 7.82 (s, 1H), 8.04-8.06 (d, 1H), 8.20-8.22 (d, 1H), 9.13 (s, 1H)

EXAMPLES 71-75

These compounds were prepared following the procedure described inexample 70. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 17. TABLE 17 Example ESI/MSm/e [(M)+] Purity (%) 71 467 100 72 467 100 73 471 98 74 437 86 75 48692

EXAMPLE 76 Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid A. Preparation of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 4.9 g (18 mmol) of4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 35.4 ml (21.6 mmol) of a 0.61 M solution of3-bromomethylfurane. After standard work-up and purification, 5.72 g(91% of yield) of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3c]pyridin-3-yl)piperidine-1-carboxylicacid ethyl ester were obtained.

B. Preparation of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine

This compound was prepared following the procedure described in example4, part D, starting with 5.72 g (16.2 mmol) of4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylicacid ethyl ester. After standard work-up, 4.3 g (93% yield) of1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine wereobtained.

C. Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 1.50 g (5.25 mmol) of1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine and 1.55 g(6.3 mmol) of 2-(2-chloroethoxy)-4-methoxybenzoic acid methyl ester.After standard work-up and purification, 0.95 g (36% yield) of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid methyl ester were obtained.

D. Preparation of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 0.95 g (1.94 mmol) of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}4methoxy-benzoic add methyl ester. After standard work-up andpurification, 0.27 g (30% yield) of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl]-ethoxy}-methoxy-benzoicacid were obtained.

Melting point=303.4-304.5° C.

NMR (300 MHz, DMSO-d6) δ=1.72-2.00 (m, 4H), 2.33-2.58 (m, 2H), 2.73-2.93(m, 3H), 3.14-3.17 (m, 2H), 3.79 (s, 3H), 4.37 (s, 2H), 5.28 (s, 3H),6.42 (s, 1H), 6.59-6.62 (s, 1H), 6.76 (s, 1H), 7.47 (s, 1H), 7.57-7.63(m, 3H), 7.78 (s, 1H), 8.00 (m, 1H), 9.00 (m, 1H)

EXAMPLES 77-80

These compounds were prepared following the procedure described inexample 76. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 18. TABLE 18 Example ESI/MSm/e [(M)+] Purity (%) 77 445 94 78 445 83 79 445 75 80 479 100

EXAMPLE 81 Preparation of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid A. Preparation of4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acidethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 4.9 g (18 mmol) of4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic add ethylester and 35.4 ml (21.6 mmol) of a 0.61 M solution of3-bromomethylfurane. After standard work-up and purification, 6.14 g(43% of yield) of4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acidethyl ester were obtained.

B. Preparation of 1-butyl-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine

This compound was prepared following the procedure described in example24, part D, starting with 6.14 g (18.6 mmol) of4-(1-butyl-1H-pyrrolo[2,3]pyridin-3-yl)piperidine-1-carboxylic add ethylester. After standard work-up, 5.45 g (100% yield) of1-butyl-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine were obtained.

C. Preparation of2-{2-[4-(1-butyl-1H-pyrrolo[2,3]pyridin-3-yl)piperidin-1-yl-ethoxy}-benzoicacid methyl ester

This compound was prepared following the procedure described in example4, part E, starting with 1.35 g (5.25 mmol) of 1-butyl-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine and 1.35 g (6.3 mmol) of2-(2-chloroethoxy)benzoic acid methyl ester. After standard work-up andpurification, 1.1 g (49% yield) of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid methyl ester were obtained.

D. Preparation of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid

This compound was prepared following the procedure described in example4, part F, starting with 1.1 g (2.57 mmol) of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid methyl ester. After standard work-up and purification, 0.42 g (42%yield) of2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]ethoxy}-benzoicacid were obtained.

Melting point=157.8-158.8° C.

NMR (300. MHz, DMSO-d6) δ=0.86-0.91 (t, 3H), 1.18-1.31 (m, 2H),1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 2.58-2.69 (m, 2H), 2.82-3.01 (m,3H), 3.19-3.23 (d, 2H), 4.21-4.25 (t, 2H), 4.41-4.45 (t, 2H), 6.69-7.04(t, 1H), 7.22-7.24 (d, 1H), 7.36-7.44 (m, 2H), 7.53-7.56 (dd, 1H),7.65-7.67 (d, 1H), 8.07-8.09 (d, 1H), 8.83 (s, 1H)

EXAMPLES 82-87

These compounds were prepared following the procedure described inexample 81. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 19. TABLE 19 Example ESI/MSm/e [(M)+] Purity (%) 82 451 100 83 451 100 84 455 100 85 421 95 86 470100 87 391 92

EXAMPLE 88 Preparation of5-{4-[1-(5-chloro-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid A. Preparation of4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester

This compound was prepared following the procedure described in example24, part C, starting with 8.7 g (31,8 mmol) of4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethylester and 5.75 ml (47.7 mmol) of 2-chloro-5-chloromethylthiophen. Afterstandard work-up and purification, 7.67 g (60% of yield) of4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicadd ethyl ester were obtained.

B. Preparation of1-(5-chlorothiophen-2-ylmethyl)-3-piperidinyl-1H-pyrrolo[2,3-c]pyridine

This compound was prepared following the procedure described in example24, part D, starting with 7.67 g (19 mmol) of4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylicacid ethyl ester. After standard work-up, 2.94 g (46% yield) of1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine.

C. Preparation of5-{4-[1-(5-chloro-hiophen-2-ylmethyl)-1H-pyrrolo[2,3]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester

This compound was prepared following the procedure described in example24, part E, starting with 0.44 g (1.32 mmol) of1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridineand 0.36 g (1.32 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethylester. After standard work-up and purification, 0.3 g (43% yield) of5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester were obtained.

D. Preparation of5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}2-methoxy-benzoicacid

This compound was prepared following the procedure described in example24, part F, starting with 0.3 g (0.57 mmol) of5-{4-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid ethyl ester. After standard work-up and purificaton, 0.2 g (60%yield) of5-{4-[1-(5-chloro-hiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoicacid were obtained.

Melting point=125.0-127.2° C.

NMR (300 MHz, DMSO-d6) δ=1.62-1.71 (m, 2H), 1.89-1.94 (m, 2H), 2.07-2.14(m, 2H), 2.71-2.82 (m, 1H), 2.87-2.95 (m, 2H), 3.47 (s, 2H), 3.80 (s,3H), 5.60 (s, 2H), 6.98 (s, 1H), 7.06-7.09 (m, 2H), 7.42-7.45 (m, 1H),7.50 (s, 1H), 7.56-7.58 (m, 2H), 8.08 (s, 1H), 8.89 (m, 1H).

EXAMPLES 89-93

These compounds were prepared following the procedure described inexample 88. They were purified by preparative HPLC triggered by MS.ESI/MS and purity data are shown in table 20. TABLE 20 Example ESI/MSm/e [(M)+] Purity (%) 89 496 68 90 526 70 91 526 62 92 530 54 93 433 20

EXAMPLE 94-99

These compounds were prepared following the procedure described inexample 89 starting with the corresponding starting materials. They werepurified by preparative HPLC triggered by MS. ESI/MS and purity data areshown in table 21. TABLE 21 Example ESI/MS m/e [(M)+] Purity (%) 94 461100 95 445 93 96 445 97 97 491 93 98 461 81 99 423 67

EXAMPLE 100 Preparation of2-(2-{4-[1-(2-ethoxyethyl)-7-hydroxy-1H-pyrrolo[2,3-b]pyrldin-3-yl]-piperidin-1-yl}-ethoxy-benzoicacid

Over a solution of 0.15 g (0.68 mmol) of 3-chloroperbenzoic acid in 3 mlof dichloromethane at 0° C., a solution of 0.3 g (0.68 mmol) of2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoicacid in 10 ml of dichloromethane was slowly added. After 2 hours at 0°C., the crude mixture was diluted with 15 ml of dichloromethane andwashed with brine. The organic phase was dried over magnesium sulphate,filtered and the solvent was removed over reduced pressure. The crudemixture was purified by chromatography over silica gel affording 0.14 g(46% yield) of2-(2-{4-[1-(2-ethoxyethyl)-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}ethoxy)-benzoicacid.

Melting point=173.8-175.1° C.

NMR (300 MHz, DMSO-d6) δ=1.01-1.06 (t, 3H), 1.95-1.99 (m, 2H), 2.22-2.33(m, 2H), 3.01-3.09 (t, 1H), 3.38-3.45 (q, 2H), 3.57-3.73 (m, 6H),3.79-3.89 (m, 2H), 4.33-4.37 (t, 2H), 4.59.4.77 (m, 2H), 6.95-6.99 (t,1H), 7.06-7.09 (dd, 1H), 7.16-7.19 (m, 1H), 7.32-7.39 (m, 3H), 7.98-8.01(d, 1H), 8.22-8.24 (d, 1H).

Also included within the scope of the present invention arepharmaceutical compositions which comprise, as the active ingredient, atleast one azaindolylpiperidine derivative of general formula 1, or apharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable carrier or diluent. Preferably thecomposition is made up in a form suitable for oral, or parenteraladministration. The pharmaceutically acceptable carriers or diluentswhich are mixed with the active compound or compounds, or salts thereof,to form the composition of this invention are well-known “per se” andthe actual excipients used depend “inter alia” on the intended method ofadministration of the compositions.

Compositions of this invention are preferably adapted for oraladministration. In this case, the compositions may take the form oftablets, capsules or effervescent granules or of liquid preparationssuch as elixirs, syrups or suspensions, all containing one or morecompounds of the invention; such preparations may be made by methodswell known in the art. The diluents which may be used in the preparationof the compositions include those liquid and solid diluents which arecompatible with the active ingredient, together with colouring orflavouring agents, if desired.

Tablets or capsules may conveniently contain between 0.2 and 500 mg,preferably from 0.5 to 100 mg, of active ingredient or the equivalentamount of a pharmaceutically acceptable salt thereof. The compounds maybe incorporated into pellets coated with an appropriate natural orsynthetic polymer known in the art to produce sustained releasecharacteristics. They can also be incorporated with polymers into tabletform to produce the same characteristics.

The liquid composition adapted for oral use may be in the form ofsolution or suspension. The solution may be an aqueous solution of anacid addition salt of the azaindolylpiperidine derivative in associationwith, for example, sucrose or sorbitol to form a syrup. The suspensionmay comprise an insoluble or microencapsulated form of an activecompound of the invention in association with water or otherpharmaceutically acceptable liquid medium together with a suspendingagent or flavouring agent.

Compositions for parenteral injection may be prepared from soluble saltsof the azaindolylpiperidine derivatives, which may or may not befreeze-dried and which may be dissolved in water or an appropriateparenteral injectable fluid.

In human therapy, the doses of the compound of general formula I dependon the desired effect and duration of treatment; adult doses aregenerally between 0.2 mg and 500 mg per day and preferably between 0.5mg and 100 mg per day. In general, the physician will decide the dosingregime taking into account the age and weight of the patient beingtreated.

Pharmacological Action

The following assays were carried out to demonstrate the excellentpharmacological activities of the compounds of the present invention.

(1) In vitro histamine H₁ receptor binding assay, to measure theaffinity of the compounds.

(2) Histamine-induced skin vascular permeability in rats, to evaluateantiallergic activity.

(3) H₁ ex vivo binding studies in mice, to assess the degree ofpenetration into the central nervous system.

(4) Measurement of blood pressure and heart rate in consciousunrestrained hypertensive rats, to monitor cardiovascular effects.

(1) Histamine-H₁ Receptor Binding Assay

The study of binding to histamine-H₁ receptors was performed in guineapig cerebellum membranes as described previously (Chang et al., J.Neurochem, 1979, 32, 1653-1663). Briefly, the membrane suspensions (160μg/ml) were incubated at 30°αC. with 0.7 nM [³H]-mepyramine anddifferent concentrations of the test compounds in a final volume of 250μl. Binding reactions were terminated by filtration after 30 min ofincubation and the bound radioactivity was determined. The non-specificbinding was measured in the presence of 10 μM of promethazine. Theaffinity of each test compound to the receptor was determined by usingat least six different concentrations run in duplicate. IC₅₀ values wereobtained by non-linear regression by use of SAS on a DEC AXP computer.TABLE 13 Histamine-H₁ receptor binding assay Compound Binding tohistamine H₁ receptor (IC₅₀, nM) Cetirizine 226 Fexofenadine 214Loratadine 360 1 240 2 560 3 225 4 403 5 695 6 190 7 205 8 405 9 150 10335 11 505 14 510 17 265 18 315 19 500 22 235 23 275 24 475 25 235 26275 28 520 36 160 37 155 43 120 44 70 45 255 50 48 54 695 61 100 63 11064 380 73 111 76 675 81 220 84 74 92 105 96 805

Our results show that the compounds of the present invention haveaffinities for the H₁ receptors very similar to the reference compoundscetirizine, fexofenadine and loratadine.

(2) Histamine-Induced Skin Vascular Permeability in Rats

Male Wistar rats (180-210 g) were treated orally with the test compoundor vehicle. Either one, four, eight or 24 hours later the rats werelightly anaesthetized with ether and a cutaneous reaction was induced bytwo intradermal injections of 50 μl of histamine (100 μg/ml) onto theback, followed by a intravenous injection of 3 ml/kg of Evan's Blue (5mg/ml), both dissolved in saline. Sixty minutes later, the rats werekilled by cervical dislocation and the back skin dissected free. Thediameter (in millimetres) of the papule was measured in two directionsand the area was calculated. Results are given as the % of inhibition ata given dose compared with the vehicle treated group.

The compounds disclosed in examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 19,24, 25, 36, 44 and 61 produced an inhibition greater than 50% of thevascular permeability induced by histamine four hours afteradministration of a dose of 3 mg/Kg of the compounds of the invention.Under the same experimental conditions, cetirizine and fexofenadineproduced an inhibition of 36% and 21%, respectively.

(3) Histamine-H₁ Receptor Ex Vivo Binding Studies in Mice

The assay was performed essentially as described by Leysen et al (DrugDevelopment Reasearch 1991, 22, 165-178) with the followingmodifications. Overnight starved male Swiss albino mice (21±2 g) weretreated orally with different doses of the test compounds (10 ml/kg,p.o.) and 90 minutes later were killed. The whole brain was dissectedout and homogenized in 10 ml of ice-cold 0.05 M Na⁺/K⁺ phosphate buffer(pH 7.4). A 1 ml aliquot of the homogenate was incubated, in triplicate,with 0.1 ml [³H]-mepyramine (2 nM final concentration, 27 Ci/mmol,Amersham) during 40 minutes at 30° C. The concentration of[³H]-mepyramine bound to the membranes was determined by immediatefiltration of the homogenates under vacuum onto glass fibre filters(Whatman GF/B) followed by three rapid rinses with 5 ml of cold buffercontaining 10 μM cold mepyramine. The radioactivity bound in the filterswas determined by liquid scintillation spectrometry. The non-specificbinding was determined by treating the animals with 30 mg/kg p.o.D-chlorpheniramine maleate. Mice treated with vehicle (methylcellulose0.5% and tween 0.1%) were used to determine the total binding.

The results of this assay, expressed as a percentage of specific bindingat a given dose of the test compound, show that the compounds of thepresent invention display little or no penetration through the bloodbrain barrier.

(4) Measurement of Blood Pressure and Heart Rate in ConsciousUnrestrained Hypertensive Rats

Blood pressure sensors were implanted just above the iliac bifurcationin the abdominal aorta of adult male spontaneously hypertensive rats(SHR). After recovery from anaesthesia, rats were housed individually incages placed on radio-frequency receivers. Amoxycillin (15 mg/kg, i.m.,after surgery) was administered to prevent infection. The rats wereallowed to recover for at least 2 weeks after transmitter implantation.Arterial blood pressure and heart rate were recorded and analysed byDataquest V system (Data Science, St. Paul, Minn.). The animals werekept on a 12:12 hours light-dark cycle during the entire recordingperiod. After 18 hours of fasting with water “ad libitum”, the animalsreceived drugs orally and were then given food. Hemodynamic recordingswere taken every 15 minutes, starting 4 hours before drug administrationand continuing up to 24 hours after. Each recording lasted 10 seconds,and the hemodynamic values of all cycles within this period wereaveraged. All the animals received all the treatments. Betweenadministrations to the same rat there was a seven day wash-out period,and a complete recovery to base-line values was ascertained. The effectsof the treatments on mean arterial blood pressure and heart rate weredetermined with one-way analysis of variance (ANOVA). A P value <0.05was considered statistically significant.

The compounds of the present invention have little or no effects onblood pressure and heart rate at doses from 3 to 30 mg/kg.

The above described results show that the compounds of the presentinvention have excellent antihistamine and antiallergic activities,which are at least comparable, and in many cases better, than those ofthe commercial antihistamines used as reference.

At the same time, the compounds of the present invention have reducedcardiovascular and central nervous system side effects. They can thus beadvantageously used for the treatment of allergic disorders, forinstance, bronchial asthma, rhinitis, conjunctivitis, dermatitis andurticaria.

The invention thus provides a method for treating an allergic disordercomprising the step of administering to a subject in need of suchtreatment an effective amount of a compound of formula I.

The invention also provides the use of the compounds of formula I in themanufacture of a medicament for the treatment of an allergic, disorder,as well as pharmaceutical compositions comprising a compound of formulaI. Some examples of suitable compositions are shown below.

EXAMPLE 101 Preparation of a Pharmaceutical Composition: Syrup

1000 bottles (150 ml volume) each containing a solution of 750 mg of5-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]-2-methoxy-benzoicacid were prepared as follows:5-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)- 750 gpiperidin-1-ylmethyl]-2-methoxy-benzoic acid glycerin 15,000 ghydrogenated castor oil-ethylene oxide 1,500 g sodium methylp-hydroxybenzoate 240 g sodium propyl p-hydroxybenzoate 60 g sodiumsaccharin 300 g flavouring q.s. sodium hydroxide q.s. pH = 4demineralised water q.s. 150 litresProcedure:

To a solution of the p-hydroxybenzoates and saccharin in 30 litres ofdemineralised water, an aqueous glycerin solution and hydrogenatedcastor oil-ethylene oxide were added. After stirring, the5-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoicacid was added and homogenised to reach complete dissolution. Afterthis, the flavouring agent was mixed into the solution with vigorousstirring, and the mixture was made up to final volume with demineralisedwater.

The resultant solution was filled into 150 ml bottles using anappropriate filling machine.

EXAMPLE 102 Preparation of a Pharmaceutical Composition: Capsules

50,000 capsules each containing 50 mg of2-methoxy-5-{4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicacid were prepared from the following formulation:2-methoxy-5-{4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3- 2,500 gb]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid magnesium stearate225 g lactose spray dried 18,350 g cross-linked sodiumcarboxymethylcellulose 900 g sodium lauryl sulphate 450 gProcedure:

2-methoxy-5-{4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoicacid, sodium lauryl sulphate, lactose and cross-linked sodiumcarboxymethylcellulose were mixed together and passed through a screenwith an opening of 0.6 mm. The magnesium stearate was added and themixture encapsulated into gelatine capsules of appropriate size.

EXAMPLE 103 Preparation of a Pharmaceutical Composition: Tablets

100,000 tablets each containing 25 mg of2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoicacid were prepared from the following formulation:2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin- 2,500 g3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid microcrystalline cellulose1,650 g lactose spray dried 9,620 g carboxymethyl starch 570 g sodiumstearyl fumarate 80 g colloidal silicon dioxide 80 gProcedure:

All the powders were passed through a screen with apertures of 0.6 mm.They were then all mixture in a suitable mixer for 30 minutes andcompressed into 145 mg tablets using 6 mm discs and flat bevelledpunches. The disintegration time of the tablets was about 60 seconds.

1. A compound of formula i

wherein: each of A, B, D and E independently represents a nitrogen atom or a —CR₁— group, with the proviso that at least one of A, B, D or E is a nitrogen atom; R₁ represents a hydrogen or a halogen atom, or a hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, monalkyalmino, dialkylamino, nitro, cyano or acylamino group, wherein a hydrocarbon chain in R₁ is optionally substituted by one or more further substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; R₂ represents a hydrogen atom or a group of formula L₃-(W₂)_(p) L₁, L₂ and L₃ each independently represents a single bond or an acyclic, straight or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms, optionally containing 1 to 3 groups independently chosen from —S—, —O— and —NR₃—, which replace a corresponding number of non-adjacent carbon atoms, wherein R₃ is chosen from hydrogen and an alkyl group; and wherein a hydrocarbon chain in L₁, L₂ or L₃ is optionally substituted by one or more substituents chosen from halogen, hydroxy, oxo, acylamino, phenyl, alkoxycarbonyl and hydroxycarbonyl groups; R₄ and R₅ each independently represents a hydrogen or halogen atom, a hydroxy group, or a group chosen from alkyl, alkoxy, alkenyl, alkynyl and phenyl, wherein each of said alkyl, alkoxy, alkenyl, alkynyl or phenyl groups is independently optionally substituted by one or more substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; X represents —O— or —NR₆—; R₆ and R₇ each independently represents a hydrogen atom, a group of formula —(CH₂)_(m)—W₃ or a group chosen from alkyl, alkenyl and alkynyl, wherein each of said alkyl, alkenyl or alkynyl groups is independently optionally substituted by one or more substituents chosen from —(CH₂)_(m)—W₃, —O—(CH₂)_(m)—W₃, S—(CH₂)_(m)—W₃, —NR₃—(CH₂)_(m)—W₃, hydroxy, oxo, halogen, alkoxy, alkylthio, amino, monoalkylamino, and dialkylamino; wherein each of the alkyl chains in the alkoxy, alkylthio, monoalkylamino and dialkylamino substituents is independently optionally substituted by one or more further substituents chosen from —(CH₂)_(m)—W₃, hydroxy, oxo, halogen, alkoxy, alkylthio, amino, monoalkylamino and dialkylamino groups; W₁, W₂ and W₃ each independently represents a 3- to 7-membered aromatic or nonaromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S, wherein the 3- to 7-membered aromatic or nonaromatic cyclic group is independently optionally fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S; wherein the each cyclic group is independently optionally substituted by one or more substituents chosen from halogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl, acylamino, carbamoyl, and alkylcarbamoyl groups; wherein each of the hydrocarbon chains and the cyclic moieties of these substituents is independently optionally substituted by one or more further substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; m is an integer from 0 to 4 n and p are independently 0 or 1 q is an integer from 1 to 9 or a N-oxide or a pharmaceutically acceptable salt thereof, with the proviso that the compound of formula I is not the tert-butyl ester of 4-(5-amino-1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidine-1-carboxylic acid.
 2. A compound according to claim 1, wherein only one or two of A, B, D or E is a nitrogen atom.
 3. A compound according to claim 2, wherein only one of D or E is a nitrogen atom.
 4. A compound according to claim 2, wherein only two of A, B, D or E is a nitrogen atom, the nitrogen atoms being at positions A and D or B and E.
 5. A compound according to claim 1, wherein each R₁, is independently chosen from a hydrogen atom, a halogen atom, an alkyl group, and an alkoxy group.
 6. A compound according to claim 5, wherein R₁, is hydrogen, chlorine, fluorine or methoxy.
 7. A compound according to claim 1, wherein each of L₁, L₂ and L₃ independently represents a single bond or an alkyl, oxyalkyl, aminoalkyl, thioalkyl or alkoxyalkyl group.
 8. A compound according to claim 7, wherein L₁ is an alkyl, oxyalkyl, aminoalkyl or thioalkyl group; L₂ is a single bond or an alkyl group; and L₃ is a single bond or an alkyl, oxyalkyl or alkoxyalkyl group.
 9. A compound according to claim 8, wherein L₁ is methyl, ethyl, n-propyl, oxyethyl, oxypropyl, aminoethyl or thioethyl; L₂ is a single bond, methyl or ethyl; and L₃ is a single bond, methyl, ethyl, n-propyl, isopropyl, butyl, oxyethyl, methoxyethyl or ethoxyethyl.
 10. A compound according to claim 1, wherein W₁ is an aromatic monocyclic group, which is optionally substituted by one or more substituents chosen from halogen atoms, alkyl and alkoxy groups.
 11. A compound according to claim 10, wherein W₁ is a phenyl, furanyl or thienyl group, and wherein W₁ is optionally substituted by one or more substituents chosen from fluorine, chlorine, bromine, methyl and methoxy.
 12. A compound according to claim 1, wherein n is
 0. 13. A compound according to claim 1, wherein W₂ is a cycloalkyl group, a phenyl group, or a 5- or 6-membered heterocyclyl group, and wherein W₂ is optionally substituted by one or more substituents chosen from halogen, alkyl and alkoxy.
 14. A compound according to claim 13, wherein W₂ is a cyclic group chosen from cyclopropyl, cyclobutyl, cyclopentyl, phenyl, tetrahydropyranyl, furanyl, thienyl, pyrrolyl, pyridinyl, oxetanyl and dioxanyl, and is optionally substituted by one or more substituents chosen from fluorine, chlorine, bromine, methyl, ethyl and methoxy.
 15. A compound according to claim 1, wherein p is 0 or R₂ is hydrogen.
 16. A compound according to claim 1, wherein R₄ and R₅ each independently represents a hydrogen or halogen atom, a C₁-C₄ alkyl group or a phenyl group, which is optionally substituted by one or more substituents chosen from halogen, alkyl and alkoxy.
 17. A compound according to claim 16, wherein R₄ and R₅ are both hydrogen.
 18. A compound according to claim 1, wherein X is —O— and R₇ is hydrogen, alkyl or a —(CH₂)_(n)-phenyl group, and wherein n is 0 or
 1. 19. A compound according to claim 18, wherein R₇ is hydrogen, methyl, ethyl, tert-butyl, phenyl or benzyl.
 20. A compound according to claim 1, wherein X is —N—R₆, and R₆ and R₇ are independently hydrogen, alkyl or a —(CH₂)_(n)-phenyl group, and wherein n is 0 or
 1. 21. A compound according to claim 20, wherein R₆ and R₇ are independently hydrogen, methyl, ethyl, tert-butyl, phenyl or benzyl.
 22. A compound according to claim 1, chosen from: 3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}benzoic acid; 3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperdine-1-yl]ethoxy}benzoic acid; 3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidin-1-ylmethyl}benzoic acid; 5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-1-ylmethyl}-2-methoxybenzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylethoxy) benzoic acid; 5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 3-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid; 2-{2-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 3-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperdin-1-ylmethyl]-benzoic acid; 2-methoxy-5-[4-(1-thiophen-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-{2-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 3-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-methoxy-5-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 3-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid; 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid; 2-(2-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid; 2,4-dimethoxy-3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid; 2-methoxy-6-(2-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid 2-{2-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid 3-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 5-[4-(1-cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 2-{2-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 3-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 5-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 2-(2-{4-[1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 4-{4-[1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-butyric acid; (2-{4-[1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic acid; 4-chloro-2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-fluorobenzoic acid; 3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid; 3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2,4-dimethoxybenzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-6-methoxybenzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxybenzoic acid; 4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 2-fluoro-5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxybenzoic acid; 3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-2-methoxybenzoic acid; 3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2,4-dimethoxybenzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-6-methoxybenzoic acid; 2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}4-methoxybenzoic acid; 2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxybenzoic acid; 4-chloro-2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 2-fluoro-5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic acid; 4-chloro-2-(2-4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-fluorobenzoic acid; 3-4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid; 3-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-2,4-dimethoxybenzoic acid; 2-2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-6-methoxybenzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}4-methoxybenzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxybenzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-chlorobenzoic acid; 5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-fluorobenzoic acid; 3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 3-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2,4-dimethoxybenzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-6-methoxybenzoic acid; 2-{2-[4-(1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 4-[4-(1-pyridin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-butyric acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic acid; 4-chloro-2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid; 4-bromo-3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]ethoxy}-4-methoxybenzoic acid; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}benzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-3-methoxy-benzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoic acid; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-chlorobenzoic acid; 5-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 4-bromo-3-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 3-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-3-methoxybenzoic acid; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic acid; 4-chloro-2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; (2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid; 2-{2-[4-[1-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 2-{2-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]ethoxy}-benzoic acid; 5-[4-(1-furan-2-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid; 4-methoxy-2-{2-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid; 2-methoxy-5-[4-(1-thiophen-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-ylmethyl]-benzoic acid; 2-(2-{4-(1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 2-(2-{4-[1-(2-ethoxyethyl)-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid; 3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylmethyl}-benzoic acid ethyl ester; 3-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-ylmethyl]benzoic acid methyl ester; 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-yl]ethoxy}-benzoic acid methyl ester; 3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidin-1-ylmethyl}-benzoic acid methyl ester, 5-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridine-1-ylmethyl}-2-methoxybenzoic acid ethyl ester, 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-ylethoxy)benzoic acid methyl ester; 5-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid ethyl ester; 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid methyl ester; 5-[4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-ylmethyl]-2-methoxybenzoic acid ethyl ester; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxybenzoic acid methyl ester; 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid methyl ester, 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoic acid methyl ester; 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester; 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxybenzoic acid ethyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ter-butyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ter-butyl ester; 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester; 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; 4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester; and 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester; or a N-oxide or a pharmaceutically acceptable salt thereof.
 23. A process for producing a compound as claimed in claim 1, comprising alkylating a compound of formula X

with a reactive intermediate of general formula XI

wherein Y is a leaving group, and optionally converting the product of the alkylation reaction into the corresponding N-oxide or pharmaceutically acceptable salt thereof.
 24. A process according to claim 23 for obtaining a compound wherein X is oxygen and R₇ is hydrogen comprising, hydrolyzing the corresponding compound of formula I wherein R₇ represents a hydrogen atom, a group of formula —(CH₂)_(m)—W₃ or a group chosen from alkyl, alkenyl, and alkynyl, wherein R₇ is optionally substituted by one or more substituents chosen from —(CH₂)_(m)—W₃, —O—(CH₂)_(m)—W₃, S—(CH₂)_(m)—W₃, —NR₃—(CH₂)_(m)—W₃, hydroxy, oxo halogen, alkoxy, alkylthio, amino, monoalkylamino, and dialkylamino; wherein each of the alkyl chains in the alkoxy, alkylthio, monoalkylamino and dialkylamino substituents is independently optionally substituted by one or more further substituents chosen from —(CH₂)_(m)—W₃, hydroxy, oxo, halogen, alkoxy, alkylthio, amino, monoalkylamino and dialkylamino groups.
 25. A process according to claim 23, wherein the compound of formula X is obtained by deprotection of a compound of formula XX

wherein R₈ represents an ethyl or tert-butyl group.
 26. A compound of formula X

wherein each of A, B, D and E independently represents a nitrogen atom or a —CR₁— group, with the proviso that at least one of A, B, D or E is a nitrogen atom; R₁ represents a hydrogen or a halogen atom, or a hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, monalkyalmino, dialkylamino, nitro, cyano or acylamino group, wherein a hydrocarbon chain in R₁ is optionally substituted by one or more further substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; R₂ represents a hydrogen atom or a group of formula L₃-(W₂)_(p) wherein L₃ represents a single bond or an acyclic, straight or branched, saturated or unsaturated hydrocarbon chain having from 1 to 10 carbon atoms, optionally containing 1 to 3 groups independently chosen from —S—, —O— and —NR₃—, which replace a corresponding number of non-adjacent carbon atoms, wherein R₃ is chosen from hydrogen and an alkyl group; and wherein a hydrocarbon chain in L₃ is optionally substituted by one or more substituents chosen from halogen, hydroxy, oxo, acylamino, phenyl, alkoxycarbonyl and hydroxycarbonyl groups; W₂ represents a 3- to 7-membered aromatic or nonaromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S, wherein the 3- to 7-membered aromatic or nonaromatic cyclic is optionally fused to another 3- to 7-membered aromatic or non-aromatic cyclic group containing from 0 to 4 heteroatoms chosen from N, O and S; wherein each cyclic group is independently optionally substituted by one or more substituents chosen from halogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, nitro, cyano, oxo, hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl, acylamino, carbamoyl, and alkylcarbamoyl groups; wherein each of the hydrocarbon chains and the cyclic moieties of these substituents is independently optionally substituted by one or more further substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; p is 0 or 1 R₄ and R₅ each independently represents a hydrogen or halogen atom, a hydroxy group, or a group chosen from alkyl, alkoxy, alkenyl, alkynyl and phenyl, wherein each of said alkyl, alkoxy, alkenyl, alkynyl, or phenyl is independently optionally substituted by one or more substituents chosen from halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups; q is an integer from 1 to 9; or a N-oxide and or a pharmaceutically acceptable salts salt thereof: with the proviso that when A is a nitrogen atom; B is a —CR₁₋ group; D and E are both —CH—; and R₂, R₄ and R₅, are all hydrogen, then R₁ cannot be an acylamino group.
 27. (canceled)
 28. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable diluent or carrier.
 29. (canceled)
 30. (canceled)
 31. A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of H₁ histamine receptors, comprising administering to said subject an effective amount of a compound as claimed in claim
 1. 32. A method according to claim 31, wherein the pathological condition or disease is chosen from bronchial asthma, allergic rhinitis, conjunctivitis, dermatitis, urticaria and any other allergic disease.
 33. A process according to claim 23, wherein the leaving group is chosen from chlorine, bromine, a methane sulphonate group, a p-toluene sulphonate group and a benzene sulphonate group. 